Publications by authors named "Toshiko Ichiye"

57 Publications

How adding a single methylene to dihydrofolate reductase can change its conformational dynamics.

J Chem Phys 2021 Apr;154(16):165103

Department of Chemistry, Georgetown University, Washington, District of Columbia 20057, USA.

Studies of the effects of pressure on proteins from piezophilic (pressure-loving) microbes compared with homologous proteins from mesophilic microbes have been relatively rare. Interestingly, such studies of dihydrofolate reductase show that a single-site mutation from an aspartic acid to a glutamic acid can reverse the pressure-dependent monotonic decrease in activity to that in a monotonic pressure-dependent activation. This residue is near the active site but is not thought to directly participate in the catalytic mechanism. Here, the ways that addition of one carbon to the entire protein could lead to such a profound difference in pressure effects are explored using molecular dynamics simulations. The results indicate that the glutamate changes the coupling between a helix and the β-sheet due to the extra flexibility of the side chain, which further changes correlated motions of other regions of the protein.
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http://dx.doi.org/10.1063/5.0047942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068499PMC
April 2021

Understanding how water models affect the anomalous pressure dependence of their diffusion coefficients.

J Chem Phys 2020 Sep;153(10):104510

Department of Chemistry, Georgetown University, Washington, DC 20057, USA.

The self-diffusion coefficient of water shows an anomalous increase with increasing hydrostatic pressure up to a broad maximum (P) near 1 kbar at 298 K, which has been attributed to pressure effects on the tetrahedral hydrogen bond network of water. Moreover, the ability of a water model to reproduce anomalous properties of water is a signature that it is reproducing the network. Here, water was simulated between 1 bar and 5 kbar using three water models, two four-site (with all charges in the molecular plane) and one single-site multipole (which accounts for out-of-molecular plane charge), that have reasonable pressure-temperature properties. For these three models, the diffusion coefficients display a maximum in the pressure dependence and the radial distribution functions show good agreement with the limited experimental structural data at high pressure that are available. In addition, a variety of properties associated with the network are examined, including hydrogen bond lifetimes and occupancies, three-body angle distributions, and tetrahedral order parameters. Results suggest that the initial increasing diffusion with pressure is because hydrogen bonds are distorted and thus weakened by pressure, but above P, the hydrogen bonds are weakened to the point it behaves more like a normal liquid. In other words, the P may be a measure of the angular strength of hydrogen bonds. In addition, since the four-site models over-predict the values of P while the multipole model under-predicts it, out-of-plane charge may improve four-site models.
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http://dx.doi.org/10.1063/5.0021472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486981PMC
September 2020

Dynamical Model for the Counteracting Effects of Trimethylamine -Oxide on Urea in Aqueous Solutions under Pressure.

J Phys Chem B 2020 03 27;124(10):1978-1986. Epub 2020 Feb 27.

Department of Chemistry, Georgetown University, Washington, D.C. 20057, United States.

Of cosolutes found in living cells, urea denatures and trimethylamine -oxide (TMAO) stabilizes proteins; furthermore, these effects cancel at a 2:1 ratio of urea to TMAO. Interestingly, cartilaginous fish use urea and TMAO as osmolytes at similar ratios at the ocean surface but with increasing fractions of TMAO at increasing depths. Here, molecular dynamics simulations of aqueous solutions with different urea:TMAO ratios show that the diffusion coefficients of water in the solutions vary with pressure if the urea:TMAO ratio is constant, but strikingly, they are almost pressure independent at the ratio found in these fish as a function of depth. This suggests that this ratio may be maintaining a homeostasis of water dynamics. In addition, diffusion is determined by hydrogen-bond lifetimes of the different species in the solution. Based on these observations, a dynamical model in terms of hydrogen-bond lifetimes is developed for the hydrogen bonding propensities of cosolutes and water in an aqueous solution to proteins. This model provides an explanation for both the counteracting effects of TMAO on urea denaturation and the depth-dependent urea:TMAO ratio found in cartilaginous fish.
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http://dx.doi.org/10.1021/acs.jpcb.9b10844DOI Listing
March 2020

Molecular Dynamics and Neutron Scattering Studies of Potassium Chloride in Aqueous Solution.

J Phys Chem B 2019 12 10;123(50):10807-10813. Epub 2019 Dec 10.

Department of Food Science , Cornell University , Ithaca , New York 14853 , United States.

Neutron diffraction with isotopic substitution (NDIS) experiments were done on both natural abundance potassium and isotopically labeled KCl heavy water solutions to characterize the solvent structuring around the potassium ion in water. Preliminary measurements suggested that the literature value for the coherent neutron scattering length (2.69 fm) for K was significantly in error. This value was remeasured using a neutron powder diffractometer and found to be 2.40 fm. This revision increases significantly the contrast between the natural abundance K and K by about 30% (from 1.0 to 1.3 fm). The experimentally determined structure factor of the potassium ion was then compared to that calculated from molecular dynamics (MD) simulations. Previous neutron scattering measurements of potassium gave a solvation number of 5.5 (see below). In this study, the NDIS and MD results are in good agreement and allowed us to derive a coordination number of 6.1 for water molecules and 0.8 for chloride ions around each K ion in 4 molal aqueous KCl solution.
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http://dx.doi.org/10.1021/acs.jpcb.9b08422DOI Listing
December 2019

Adaptations for Pressure and Temperature Effects on Loop Motion in and Dihydrofolate Reductase.

High Press Res 2019 5;39(2):225-237. Epub 2019 Mar 5.

Department of Chemistry, Georgetown University, Washington, DC 20057.

Determining how enzymes in piezophilic microbes function at high pressure can give insights into how life adapts to living at high pressure. Here, the effects of pressure and temperature on loop motions are compared (Ec) and (Mp) dihydrofolate reductase (DHFR) via molecular dynamics simulations at combinations of the growth temperature and pressure of the two organisms. Analysis indicates that a flexible CD loop in MpDHFR is an adaptation for cold because it makes the adenosine binding subdomain more flexible. Also, analysis indicates that the Thr113-Glu27 hydrogen bond in MpDHFR is an adaptation for high pressure because it provides flexibility within the loop subdomain compared to the very strong Thr113-Asp27 hydrogen bond in EcDHFR, and affects the correlation of the Met20 and GH loops. In addition, the results suggest that temperature might affect external loops more strongly while pressure might affect motion between elements within the protein.
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http://dx.doi.org/10.1080/08957959.2019.1584799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662930PMC
March 2019

Effects of Pressure and Temperature on the Atomic Fluctuations of Dihydrofolate Reductase from a Psychropiezophile and a Mesophile.

Int J Mol Sci 2019 Mar 22;20(6). Epub 2019 Mar 22.

Department of Chemistry, Georgetown University, Washington, DC 20057, USA.

Determining the effects of extreme conditions on proteins from "extremophilic" and mesophilic microbes is important for understanding how life adapts to living at extremes as well as how extreme conditions can be used for sterilization and food preservation. Previous molecular dynamics simulations of dihydrofolate reductase (DHFR) from a psychropiezophile (cold- and pressure-loving), (Mp), and a mesophile, (Ec), at various pressures and temperatures indicate that atomic fluctuations, which are important for enzyme function, increase with both temperature and pressure. Here, the factors that cause increases in atomic fluctuations in the simulations are examined. The fluctuations increase with temperature not only because of greater thermal energy and thermal expansion of the protein but also because hydrogen bonds between protein atoms are weakened. However, the increase in fluctuations with pressure cannot be due to thermal energy, which remains constant, nor the compressive effects of pressure, but instead, the hydrogen bonds are also weakened. In addition, increased temperature causes larger increases in fluctuations of the loop regions of MpDHFR than EcDHFR, and increased pressure causes both increases and decreases in fluctuations of the loops, which differ between the two.
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http://dx.doi.org/10.3390/ijms20061452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470811PMC
March 2019

Reduction potential calculations of the Fe-S clusters in Thermus thermophilus respiratory complex I.

J Comput Chem 2019 05 29;40(12):1248-1256. Epub 2019 Jan 29.

Department of Chemistry, Georgetown University, Washington, District of Columbia, 20057.

Respiratory complex I facilitates electron transfer from NADH to quinone over ~95 Å through a chain of seven iron-sulfur (Fe-S) clusters in the respiratory chain. In this study, the reduction potentials of the Fe-S clusters in Thermus thermophilus complex I are calculated using a Density Functional Theory + Poisson-Boltzmann method. Our results indicate that the reduction potentials are influenced by a variety of factors including the clusters being deeply buried in the complex and the protonation state of buried ionizable residues. In addition, as several of the ionizable side chains have predicted pK values near pH 7, relatively small structural fluctuations could lead to significant (0.2 V) shifts in the reduction potential of several of the Fe-S clusters, suggesting a dynamic mechanism for electron transfer. Moreover, the method used here is a useful computational tool to study other questions about complex I. © 2019 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcc.25785DOI Listing
May 2019

Dynamical Effects of Trimethylamine N-Oxide on Aqueous Solutions of Urea.

J Phys Chem B 2019 02 28;123(5):1108-1115. Epub 2019 Jan 28.

Department of Chemistry , Georgetown University , Washington, D.C. 20057 , United States.

Trimethylamine N-oxide (TMAO) stabilizes protein structures, whereas urea destabilizes proteins, and their opposing effects can be counteracted at a 1:2 ratio of TMAO to urea. To investigate how they affect solution dynamics, molecular dynamics simulations have been carried out for aqueous solutions of TMAO and urea at different concentrations. In the binary solutions, urea mainly slows the diffusion of waters that are hydrogen bonded to it (i.e., hydration water), whereas TMAO dramatically slows the diffusion of both hydration water and bulk water because of long-lived TMAO-water hydrogen bonds. In the ternary solutions, because TMAO decreases the diffusion rate of bulk water, the lifetimes of not only water-water but also urea-water hydrogen bonds increase. In addition, the constant forming and breaking of short lifetime hydrogen bonds between urea and water appears to impart energy into the bulk, whereas the long lifetime hydrogen bonds between TMAO and water slows down the bulk, resulting in the compensating effects on bulk water in the ternary solution. This suggests that the counteracting effects of TMAO on urea denaturation may be both to make longer lived hydrogen bonds to water and to counter the energizing effects of urea on bulk water.
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http://dx.doi.org/10.1021/acs.jpcb.8b09874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085122PMC
February 2019

Diffusion of aqueous solutions of ionic, zwitterionic, and polar solutes.

J Chem Phys 2018 Jun;148(22):222827

Department of Chemistry, Georgetown University, Washington, DC 20057, USA.

The properties of aqueous solutions of ionic, zwitterionic, and polar solutes are of interest to many fields. For instance, one of the many anomalous properties of aqueous solutions is the behavior of water diffusion in different monovalent salt solutions. In addition, solutes can affect the stabilities of macromolecules such as proteins in aqueous solution. Here, the diffusivities of aqueous solutions of sodium chloride, potassium chloride, tri-methylamine oxide (TMAO), urea, and TMAO-urea are examined in molecular dynamics simulations. The decrease in the diffusivity of water with the concentration of simple ions and urea can be described by a simple model in which the water molecules hydrogen bonded to the solutes are considered to diffuse at the same rate as the solutes, while the remainder of the water molecules are considered to be bulk and diffuse at almost the same rate as pure water. On the other hand, the decrease in the diffusivity of water with the concentration of TMAO is apparently affected by a decrease in the diffusion rate of the bulk water molecules in addition to the decrease due to the water molecules hydrogen bonded to TMAO. In other words, TMAO enhances the viscosity of water, while urea barely affects it. Overall, this separation of water molecules into those that are hydrogen bonded to solute and those that are bulk can provide a useful means of understanding the short- and long-range effects of solutes on water.
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http://dx.doi.org/10.1063/1.5023004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902334PMC
June 2018

Quasiharmonic Analysis of the Energy Landscapes of Dihydrofolate Reductase from Piezophiles and Mesophiles.

J Phys Chem B 2018 05 8;122(21):5527-5533. Epub 2018 Feb 8.

Department of Chemistry , Georgetown University , Washington , DC 20057 , United States.

A quasiharmonic analysis (QHA) method is used to compare the potential energy landscapes of dihydrofolate reductase (DHFR) from a piezophile (pressure-loving organism), Moritella profunda (Mp), and a mesophile, Escherichia coli (Ec). The QHA method considers atomic fluctuations of the protein as motions of an atom in a local effective potential created by neighboring atoms and quantitates it in terms of effective force constants, isothermal compressibilities, and thermal expansivities. The analysis indicates that the underlying potential energy surface of MpDHFR is inherently softer than that of EcDHFR. In addition, on picosecond time scales, the energy surfaces become more similar under the growth conditions of Mp and Ec. On these time scales, DHFR behaves as expected; namely, increasing temperature makes the effective energy minimum less steep because thermal fluctuations increase the available volume, whereas increasing pressure steepens it because compression reduces the available volume. Our longer simulations show that, on nanosecond time scales, increasing temperature has a similar effect as on picosecond time scales because thermal fluctuations increase the volume even more on a longer time scale. However, these simulations also indicate that, on nanosecond time scales, pressure makes the local potential less steep, contrary to picosecond time scales. Further examination of the QHA indicates the nanosecond pressure response may originate at picosecond time scales at the exterior of the protein, which suggests that protein-water interactions may be involved. The results may lead to understanding adaptations in enzymes made by piezophiles that enable them to function at higher pressures.
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http://dx.doi.org/10.1021/acs.jpcb.7b11838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287743PMC
May 2018

Enzymes from piezophiles.

Authors:
Toshiko Ichiye

Semin Cell Dev Biol 2018 12 1;84:138-146. Epub 2018 Feb 1.

Department of Chemistry, Georgetown University, Washington, DC, 20057, United States.

The discovery of microbial communities in extreme conditions that would seem hostile to life leads to the question of how the molecules making up these microbes can maintain their structure and function. While microbes that live under extremes of temperature have been heavily studied, those that live under extremes of pressure, or "piezophiles", are now increasingly being studied because of advances in sample collection and high-pressure cells for biochemical and biophysical measurements. Here, adaptations of enzymes in piezophiles against the effects of pressure are discussed in light of recent experimental and computational studies. However, while concepts from studies of enzymes from temperature extremophiles can provide frameworks for understanding adaptations by piezophile enzymes, the effects of temperature and pressure on proteins differ in significant ways. Thus, the state of the knowledge of adaptation in piezophile enzymes is still in its infancy and many more experiments and computational studies on different enzymes from a variety of piezophiles are needed.
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http://dx.doi.org/10.1016/j.semcdb.2018.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050138PMC
December 2018

Building better water models using the shape of the charge distribution of a water molecule.

J Chem Phys 2017 Nov;147(19):194103

Department of Chemistry, Georgetown University, Washington, DC 20057, USA.

The unique properties of liquid water apparently arise from more than just the tetrahedral bond angle between the nuclei of a water molecule since simple three-site models of water are poor at mimicking these properties in computer simulations. Four- and five-site models add partial charges on dummy sites and are better at modeling these properties, which suggests that the shape of charge distribution is important. Since a multipole expansion of the electrostatic potential describes a charge distribution in an orthogonal basis set that is exact in the limit of infinite order, multipoles may be an even better way to model the charge distribution. In particular, molecular multipoles up to the octupole centered on the oxygen appear to describe the electrostatic potential from electronic structure calculations better than four- and five-site models, and molecular multipole models give better agreement with the temperature and pressure dependence of many liquid state properties of water while retaining the computational efficiency of three-site models. Here, the influence of the shape of the molecular charge distribution on liquid state properties is examined by correlating multipoles of non-polarizable water models with their liquid state properties in computer simulations. This will aid in the development of accurate water models for classical simulations as well as in determining the accuracy needed in quantum mechanical/molecular mechanical studies and ab initio molecular dynamics simulations of water. More fundamentally, this will lead to a greater understanding of how the charge distribution of a water molecule leads to the unique properties of liquid water. In particular, these studies indicate that p-orbital charge out of the molecular plane is important.
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http://dx.doi.org/10.1063/1.4986070DOI Listing
November 2017

Quasiharmonic analysis of protein energy landscapes from pressure-temperature molecular dynamics simulations.

J Chem Phys 2017 Sep;147(12):125103

Department of Chemistry, Georgetown University, Washington, DC 20057, USA.

Positional fluctuations of an atom in a protein can be described as motion in an effective local energy minimum created by the surrounding protein atoms. The dependence of atomic fluctuations on both temperature (T) and pressure (P) has been used to probe the nature of these minima, which are generally described as harmonic in experiments such as x-ray crystallography and neutron scattering. Here, a quasiharmonic analysis method is presented in which the P-T dependence of atomic fluctuations is in terms of an intrinsic isobaric thermal expansivity α and an intrinsic isothermal compressibility κ. The method is tested on previously reported mean-square displacements from P-T molecular dynamics simulations of lysozyme, which were interpreted to have a pressure-independent dynamical transition T near 200 K and a change in the pressure dependence near 480 MPa. Our quasiharmonic analysis of the same data shows that the P-T dependence can be described in terms of α and κ where below T, the temperature dependence is frozen at the T value. In addition, the purported transition at 480 MPa is reinterpreted as a consequence of the pressure dependence of T and the quasiharmonic frequencies. The former also indicates that barrier heights between substates are pressure dependent in these data. Furthermore, the insights gained from this quasiharmonic analysis, which was of the energy landscape near the native state of a protein, suggest that similar analyses of other simulations may be useful in understanding such phenomena as pressure-induced protein unfolding.
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http://dx.doi.org/10.1063/1.5003823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942443PMC
September 2017

Extreme biophysics: Enzymes under pressure.

J Comput Chem 2017 06 19;38(15):1174-1182. Epub 2017 Jan 19.

Department of Chemistry, Georgetown University, Washington, DC, 20057.

A critical question about piezophilic (pressure-loving) microbes is how their constituent molecules maintain function under high pressure. Here, factors are examined that may lead to the increased activity under pressure in dihydrofolate reductase from the piezophilic Moritella profunda compared to the homologous enzyme from the mesophilic Escherichia coli. Molecular dynamics simulations are performed at various temperatures and pressures to examine how pressure affects the flexibility of the enzymes from these two microbes, since both stability and flexibility are necessary for enzyme activity. The results suggest that collective motions on the 10-ns timescale are responsible for the flexibility necessary for "corresponding states" activity at the growth conditions of the parent organism. In addition, the results suggest that while the lower stability of many enzymes from deep-sea microbes may be an adaptation for greater flexibility at low temperatures, high pressure may enhance their adaptation to low temperatures. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcc.24737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334844PMC
June 2017

What makes proteins work: exploring life in P-T-X.

Authors:
Toshiko Ichiye

Phys Biol 2016 11 15;13(6):063001. Epub 2016 Nov 15.

Department of Chemistry, Georgetown University, Washington, DC 20057, USA.

Although considerable progress has been made in the molecular biophysics of proteins, it is still not possible to reliably design an enzyme for a given function. The current understanding of enzyme function is that both structure and flexibility are important. Much attention has been focused recently on protein folding and thus structure, spurred on by insights from the folding funnel concept. For experimental studies of protein folding, variations in temperature (T) and chemical composition (X) of the solution have been traditionally exploited, although more recent studies using variations in pressure (P) made possible through new instrumentation have led to a deeper understanding of the energy landscape of protein folding. Other work has shown that flexibility is also essential for enzymes, although it is still not clear what type is important. Another avenue has been to take advantage of 'Nature's laboratory' by exploring homologous proteins from organisms that live in extreme conditions, or 'extremophiles'. While the most studied extremophiles live at extremes of T and X, recent exploration of deep-sea environments has led to the discovery of organisms living under high P, or 'piezophiles'. An exploration of targeted enzymes from organisms with various P-T-X growth conditions coupled with advances in biophysical instrumentation and computer simulations that allow studies of these enzymes at different P-T-X conditions may lead to a better understanding of 'flexibility' and to general design criteria for active enzymes. Preface. Kamal Shukla's great contribution to science has been his vision that physical sciences could bring new insights to biological sciences, and that the marriage of methodologies, particularly theoretical/computational with experimental, was needed to tackle the complexities of biology. Furthermore, his openness to new methods and different ideas outside the current fad has helped make his vision a reality. In my remarks below, I have not tried to limit myself to projects that I know Kamal had sponsored, nor have I tried to highlight all that he has sponsored. Instead, everything I mention has been influenced directly or indirectly by his efforts. Perhaps the indirect influences are most telling, because they would not have happened without Kamal.
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http://dx.doi.org/10.1088/1478-3975/13/6/063001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5156322PMC
November 2016

A single-site multipole model for liquid water.

J Chem Phys 2016 Jul;145(3):034501

Department of Chemistry, Georgetown University, Washington, DC 20057, USA.

Accurate and efficient empirical potential energy models that describe the atomistic interactions between water molecules in the liquid phase are essential for computer simulations of many problems in physics, chemistry, and biology, especially when long length or time scales are important. However, while models with non-polarizable partial charges at four or five sites in a water molecule give remarkably good values for certain properties, deficiencies have been noted in other properties and increasing the number of sites decreases computational efficiency. An alternate approach is to utilize a multipole expansion of the electrostatic potential due to the molecular charge distribution, which is exact outside the charge distribution in the limits of infinite distances or infinite orders of multipoles while partial charges are a qualitative representation of electron density as point charges. Here, a single-site multipole model of water is presented, which is as fast computationally as three-site models but is also more accurate than four- and five-site models. The dipole, quadrupole, and octupole moments are from quantum mechanical-molecular mechanical calculations so that they account for the average polarization in the liquid phase, and represent both the in-plane and out-of-plane electrostatic potentials of a water molecule in the liquid phase. This model gives accurate thermodynamic, dynamic, and dielectric properties at 298 K and 1 atm, as well as good temperature and pressure dependence of these properties.
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http://dx.doi.org/10.1063/1.4958621DOI Listing
July 2016

Molecular Multipole Potential Energy Functions for Water.

J Phys Chem B 2016 Mar 24;120(8):1833-42. Epub 2015 Nov 24.

Department of Chemistry, Georgetown University , Washington, DC 20057, United States.

Water is the most common liquid on this planet, with many unique properties that make it essential for life as we know it. These properties must arise from features in the charge distribution of a water molecule, so it is essential to capture these features in potential energy functions for water to reproduce its liquid state properties in computer simulations. Recently, models that utilize a multipole expansion located on a single site in the water molecule, or "molecular multipole models", have been shown to rival and even surpass site models with up to five sites in reproducing both the electrostatic potential around a molecule and a variety of liquid state properties in simulations. However, despite decades of work using multipoles, confusion still remains about how to truncate the multipole expansions efficiently and accurately. This is particularly important when using molecular multipole expansions to describe water molecules in the liquid state, where the short-range interactions must be accurate, because the higher order multipoles of a water molecule are large. Here, truncation schemes designed for a recent efficient algorithm for multipoles in molecular dynamics simulations are assessed for how well they reproduce results for a simple three-site model of water when the multipole moments and Lennard-Jones parameters of that model are used. In addition, the multipole analysis indicates that site models that do not account for out-of-plane electron density overestimate the stability of a non-hydrogen-bonded conformation, leading to serious consequences for the simulated liquid.
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http://dx.doi.org/10.1021/acs.jpcb.5b09565DOI Listing
March 2016

Protein dynamics and the all-ferrous [Fe4 S4 ] cluster in the nitrogenase iron protein.

Protein Sci 2016 Jan 1;25(1):12-8. Epub 2015 Sep 1.

Department of Chemistry, Georgetown University, Washington, District of Columbia, 20057.

In nitrogen fixation by Azotobacter vinelandii nitrogenase, the iron protein (FeP) binds to and subsequently transfers electrons to the molybdenum-FeP, which contains the nitrogen fixation site, along with hydrolysis of two ATPs. However, the nature of the reduced state cluster is not completely clear. While reduced FeP is generally thought to contain an [Fe4 S4 ](1+) cluster, evidence also exists for an all-ferrous [Fe4 S4 ](0) cluster. Since the former indicates a single electron is transferred per two ATPs hydrolyzed while the latter indicates two electrons could be transferred per two ATPs hydrolyzed, an all-ferrous [Fe4 S4 ](0) cluster in FeP is potenially two times more efficient. However, the 1+/0 reduction potential has been measured in the protein at both 460 and 790 mV, causing the biological significance to be questioned. Here, "density functional theory plus Poisson Boltzmann" calculations show that cluster movement relative to the protein surface observed in the crystal structures could account for both measured values. In addition, elastic network mode analysis indicates that such movement occurs in low frequency vibrations of the protein, implying protein dynamics might lead to variations in reduction potential. Furthermore, the different reductants used in the conflicting measurements of the reduction potential could be differentially affecting the protein dynamics. Moreover, even if the all-ferrous cluster is not the biologically relevant cluster, mutagenesis to stabilize the conformation with the more exposed cluster may be useful for bioengineering more efficient enzymes.
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http://dx.doi.org/10.1002/pro.2772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815322PMC
January 2016

The Surface Potential of the Water-Vapor Interface from Classical Simulations.

J Phys Chem B 2015 Jul 5;119(29):9114-22. Epub 2015 Mar 5.

Department of Chemistry, Georgetown University, Washington, DC 20057, United States.

The electrochemical surface potential across the water-vapor interface provides a measure of the orientation of water molecules at the interface. However, the large discrepancies between surface potentials calculated from ab initio (AI) and classical molecular dynamics (MD) simulations indicate that what is being calculated may be relevant to different test probes. Although a method for extracting the electrochemical surface potential from AIMD simulations has been given, methods for MD simulations have not been clarified. Here, two methods for extracting the surface potential relevant to electrochemical measurements from MD simulations are presented. This potential is shown to be almost entirely due to the dipole contribution. In addition, the molecular origin of the dipole contribution is explored by using different potential energy functions for water. The results here show that the dipole contribution arises mainly from distortions in the hydration shell of the full hydrogen bonded waters on the liquid side of the interface, which is determined by the charge distribution of the water model. Disturbingly, the potential varies by 0.4 eV depending on the model. Although there is still no consensus on what that charge distribution should be, recent results indicate that it contains both a large quadrupole and negative charge out of the molecular plane, i.e., three-dimensional (3D) charge. Water models with 3D charge give the least distortion of the hydration shell and the best agreement with experimental surface potentials, although there is still uncertainty in the experimental values.
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http://dx.doi.org/10.1021/jp508878vDOI Listing
July 2015

Hydrophobic hydration and the anomalous partial molar volumes in ethanol-water mixtures.

J Chem Phys 2015 Feb;142(6):064501

Department of Chemistry, Georgetown University, Washington, District of Columbia 20057, USA.

The anomalous behavior in the partial molar volumes of ethanol-water mixtures at low concentrations of ethanol is studied using molecular dynamics simulations. Previous work indicates that the striking minimum in the partial molar volume of ethanol VE as a function of ethanol mole fraction XE is determined mainly by water-water interactions. These results were based on simulations that used one water model for the solute-water interactions but two different water models for the water-water interactions. This is confirmed here by using two more water models for the water-water interactions. Furthermore, the previous work indicates that the initial decrease is caused by association of the hydration shells of the hydrocarbon tails, and the minimum occurs at the concentration where all of the hydration shells are touching each other. Thus, the characteristics of the hydration of the tail that cause the decrease and the features of the water models that reproduce this type of hydration are also examined here. The results show that a single-site multipole water model with a charge distribution that mimics the large quadrupole and the p-orbital type electron density out of the molecular plane has "brittle" hydration with hydrogen bonds that break as the tails touch, which reproduces the deep minimum. However, water models with more typical site representations with partial charges lead to flexible hydration that tends to stay intact, which produces a shallow minimum. Thus, brittle hydration may play an essential role in hydrophobic association in water.
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http://dx.doi.org/10.1063/1.4906750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5848694PMC
February 2015

The molecular charge distribution, the hydration shell, and the unique properties of liquid water.

J Chem Phys 2014 Dec;141(24):244504

Department of Chemistry, Georgetown University, Washington DC 20057, USA.

The most essential features of a water molecule that give rise to its unique properties are examined using computer simulations of different water models. The charge distribution of a water molecule characterized by molecular multipoles is quantitatively linked to the liquid properties of water via order parameters for the degree (S(2)) and symmetry (ΔS(2)) of the tetrahedral arrangement of the nearest neighbors, or "hydration shell." ΔS(2) also appears to determine the long-range tetrahedral network and interfacial structure. From the correlations, some models are shown to be unable to reproduce certain properties due to the limitations of the model itself rather than the parameterization, which indicates that they are lacking essential molecular features. Moreover, since these properties depend not only on S(2) but also on ΔS(2), the long-range structure in these models may be incorrect. Based on the molecular features found in the models that are best able to reproduce liquid properties, the most essential features of a water molecule in liquid water appear to be a charge distribution with a large dipole, a large quadrupole, and negative charge out of the molecular plane, as well as a symmetrically ordered tetrahedral hydration shell that results from this charge distribution. The implications for modeling water are also discussed.
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http://dx.doi.org/10.1063/1.4904263DOI Listing
December 2014

Web-based computational chemistry education with CHARMMing III: Reduction potentials of electron transfer proteins.

PLoS Comput Biol 2014 Jul 24;10(7):e1003739. Epub 2014 Jul 24.

Department of Chemistry, Georgetown University, Washington, D.C., United States of America.

A module for fast determination of reduction potentials, E°, of redox-active proteins has been implemented in the CHARMM INterface and Graphics (CHARMMing) web portal (www.charmming.org). The free energy of reduction, which is proportional to E°, is composed of an intrinsic contribution due to the redox site and an environmental contribution due to the protein and solvent. Here, the intrinsic contribution is selected from a library of pre-calculated density functional theory values for each type of redox site and redox couple, while the environmental contribution is calculated from a crystal structure of the protein using Poisson-Boltzmann continuum electrostatics. An accompanying lesson demonstrates a calculation of E°. In this lesson, an ionizable residue in a [4Fe-4S]-protein that causes a pH-dependent E° is identified, and the E° of a mutant that would test the identification is predicted. This demonstration is valuable to both computational chemistry students and researchers interested in predicting sequence determinants of E° for mutagenesis.
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http://dx.doi.org/10.1371/journal.pcbi.1003739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110074PMC
July 2014

Web-based computational chemistry education with CHARMMing I: Lessons and tutorial.

PLoS Comput Biol 2014 Jul 24;10(7):e1003719. Epub 2014 Jul 24.

Department of Chemistry, University of South Florida, Tampa, Florida, United States of America.

This article describes the development, implementation, and use of web-based "lessons" to introduce students and other newcomers to computer simulations of biological macromolecules. These lessons, i.e., interactive step-by-step instructions for performing common molecular simulation tasks, are integrated into the collaboratively developed CHARMM INterface and Graphics (CHARMMing) web user interface (http://www.charmming.org). Several lessons have already been developed with new ones easily added via a provided Python script. In addition to CHARMMing's new lessons functionality, web-based graphical capabilities have been overhauled and are fully compatible with modern mobile web browsers (e.g., phones and tablets), allowing easy integration of these advanced simulation techniques into coursework. Finally, one of the primary objections to web-based systems like CHARMMing has been that "point and click" simulation set-up does little to teach the user about the underlying physics, biology, and computational methods being applied. In response to this criticism, we have developed a freely available tutorial to bridge the gap between graphical simulation setup and the technical knowledge necessary to perform simulations without user interface assistance.
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http://dx.doi.org/10.1371/journal.pcbi.1003719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109840PMC
July 2014

Assessment of Quantum Mechanical Methods for Copper and Iron Complexes by Photoelectron Spectroscopy.

J Chem Theory Comput 2014 Mar 22;10(3):1283-1291. Epub 2014 Jan 22.

Department of Chemistry, Georgetown University , Washington, DC 20057, United States.

Broken-symmetry density functional theory (BS-DFT) calculations are assessed for redox energetics [Cu(SCH)], [Cu(NCS)], [FeCl], and [Fe(SCH)] against vertical detachment energies (VDE) from valence photoelectron spectroscopy (PES), as a prelude to studies of metalloprotein analogs. The M06 and B3LYP hybrid functionals give VDE that agree with the PES VDE for the Fe complexes, but both underestimate it by ∼400 meV for the Cu complexes; other hybrid functionals give VDEs that are an increasing function of the amount of Hartree-Fock (HF) exchange and so cannot show good agreement for both Cu and Fe complexes. Range-separated (RS) functionals appear to give a better distribution of HF exchange since the negative HOMO energy is approximately equal to the VDEs but also give VDEs dependent on the amount of HF exchange, sometimes leading to ground states with incorrect electron configurations; the LRC-PBEh functional reduced to 10% HF exchange at short-range give somewhat better values for both, although still ∼150 meV too low for the Cu complexes and ∼50 meV too high for the Fe complexes. Overall, the results indicate that while HF exchange compensates for self-interaction error in DFT calculations of both Cu and Fe complexes, too much may lead to more sensitivity to nondynamical correlation in the spin-polarized Fe complexes.
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http://dx.doi.org/10.1021/ct400842pDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3958136PMC
March 2014

Identifying sequence determinants of reduction potentials of metalloproteins.

J Biol Inorg Chem 2013 Aug 21;18(6):599-608. Epub 2013 May 21.

Department of Chemistry, Georgetown University, Box 571227, Washington, DC 20057-1227, USA.

The reduction potential of an electron transfer protein is one of its most important functional characteristics. Although the type of redox site and the protein fold are the major determinants of the reduction potential of a redox-active protein, its amino acid sequence may tune the reduction potential as well. Thus, homologous proteins can often be divided into different classes, with each class characterized by a biological function and a reduction potential. Site-specific mutagenesis of the sequence determinants of the differences in the reduction potential between classes should change the reduction potential of a protein in one class to that of the other class. Here, a procedure is presented that combines energetic and bioinformatic analysis of homologous proteins to identify sequence determinants that are also good candidates for site-specific mutations, using the [4Fe-4S] ferredoxins and the [4Fe-4S] high-potential iron-sulfur proteins as examples. This procedure is designed to guide site-specific mutations or more computationally expensive studies, such as molecular dynamics simulations. To make the procedure more accessible to the general scientific community, it is being implemented into CHARMMing, a Web-based portal, with a library of density functional theory results for the redox site that are used in the setting up of Poisson-Boltzmann continuum electrostatics calculations for the protein energetics.
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http://dx.doi.org/10.1007/s00775-013-1004-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3723707PMC
August 2013

Identifying residues that cause pH-dependent reduction potentials.

Biochemistry 2013 May 24;52(18):3022-4. Epub 2013 Apr 24.

Laboratory of Computational Biology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.

The pH dependence of the reduction potential E° for a metalloprotein indicates that the protonation state of at least one residue near the redox site changes and may be important for its activity. The responsible residue is usually identified by site-specific mutagenesis, which may be time-consuming. Here, the titration of E° for Chromatium vinosum high-potential iron-sulfur protein is predicted to be in good agreement with experiment using density functional theory and Poisson-Boltzmann calculations if only the sole histidine undergoes changes in protonation. The implementation of this approach into CHARMMing, a user-friendly web-based portal, allows users to identify residues in other proteins causing similar pH dependence.
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http://dx.doi.org/10.1021/bi4002858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691860PMC
May 2013

Effects of microcomplexity on hydrophobic hydration in amphiphiles.

J Am Chem Soc 2013 Apr 22;135(13):4918-21. Epub 2013 Mar 22.

Department of Chemistry, Georgetown University , Washington, D.C. 20057, United States.

Hydrophobic hydration is critical in biology as well as many industrial processes. Here, computer simulations of ethanol/water mixtures show that a three-stage mechanism of dehydration of ethanol explains the anomalous concentration dependence of the thermodynamic partial molar volumes, as well as recent data from neutron diffraction and Raman scattering. Moreover, the simulations show that the breakdown of hydrophobic hydration shells, whose structure is determined by the unique molecular properties of water, is caused by the microcomplexity of the environment and may be representative of early events in protein folding and structure stabilization in aqueous solutions.
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http://dx.doi.org/10.1021/ja312504qDOI Listing
April 2013

Characterizing the effects of the protein environment on the reduction potentials of metalloproteins.

J Biol Inorg Chem 2013 Jan 15;18(1):103-10. Epub 2012 Nov 15.

Department of Chemistry, Georgetown University, Box 571227, Washington, DC 20057-1227, USA.

The reduction potentials of electron transfer proteins are critically determined by the degree of burial of the redox site within the protein and the degree of permanent polarization of the polypeptide around the redox site. Although continuum electrostatics calculations of protein structures can predict the net effect of these factors, quantifying each individual contribution is a difficult task. Here, the burial of the redox site is characterized by a dielectric radius R(p) (a Born-type radius for the protein), the polarization of the polypeptide is characterized by an electret potential ϕ(p) (the average electrostatic potential at the metal atoms), and an electret-dielectric spheres (EDS) model of the entire protein is then defined in terms of R(p) and ϕ(p). The EDS model shows that for a protein with a redox site of charge Q, the dielectric response free energy is a function of Q(2), while the electret energy is a function of Q. In addition, R(p) and ϕ(p) are shown to be characteristics of the fold of a protein and are predictive of the most likely redox couple for redox sites that undergo different redox couples.
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http://dx.doi.org/10.1007/s00775-012-0955-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567609PMC
January 2013

Calculating standard reduction potentials of [4Fe-4S] proteins.

J Comput Chem 2013 Mar 1;34(7):576-82. Epub 2012 Nov 1.

Department of Chemistry, Georgetown University, Box 571227, Washington, DC 20057-1227, USA.

The oxidation-reduction potentials of electron transfer proteins determine the driving forces for their electron transfer reactions. Although the type of redox site determines the intrinsic energy required to add or remove an electron, the electrostatic interaction energy between the redox site and its surrounding environment can greatly shift the redox potentials. Here, a method for calculating the reduction potential versus the standard hydrogen electrode, E°, of a metalloprotein using a combination of density functional theory and continuum electrostatics is presented. This work focuses on the methodology for the continuum electrostatics calculations, including various factors that may affect the accuracy. The calculations are demonstrated using crystal structures of six homologous HiPIPs, which give E° that are in excellent agreement with experimental results.
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http://dx.doi.org/10.1002/jcc.23169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3570669PMC
March 2013

Understanding rubredoxin redox sites by density functional theory studies of analogues.

J Phys Chem A 2012 Sep 27;116(35):8918-24. Epub 2012 Aug 27.

Department of Chemistry, Georgetown University, Washington, DC 20057, USA.

Determining the redox energetics of redox site analogues of metalloproteins is essential in unraveling the various contributions to electron transfer properties of these proteins. Since studies of the [4Fe-4S] analogues show that the energies are dependent on the ligand dihedral angles, broken symmetry density functional theory (BS-DFT) with the B3LYP functional and double-ζ basis sets calculations of optimized geometries and electron detachment energies of [1Fe] rubredoxin analogues are compared to crystal structures and gas-phase photoelectron spectroscopy data, respectively, for [Fe(SCH(3))(4)](0/1-/2-), [Fe(S(2)-o-xyl)(2)](0/1-/2-), and Na(+)[Fe(S(2)-o-xyl)(2)](1-/2-) in different conformations. In particular, the study of Na(+)[Fe(S(2)-o-xyl)(2)](1-/2-) is the only direct comparison of calculated and experimental gas phase detachment energies for the 1-/2- couple found in the rubredoxins. These results show that variations in the inner sphere energetics by up to ∼0.4 eV can be caused by differences in the ligand dihedral angles in either or both redox states. Moreover, these results indicate that the protein stabilizes the conformation that favors reduction. In addition, the free energies and reorganization energies of oxidation and reduction as well as electrostatic potential charges are calculated, which can be used as estimates in continuum electrostatic calculations of electron transfer properties of [1Fe] proteins.
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http://dx.doi.org/10.1021/jp3057509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3443601PMC
September 2012