Publications by authors named "Michelle A Sahai"

16 Publications

  • Page 1 of 1

The Role of Dopamine in the Stimulant Characteristics of Novel Psychoactive Substances (NPS)-Neurobiological and Computational Assessment Using the Case of Desoxypipradrol (2-DPMP).

Front Pharmacol 2020 5;11:806. Epub 2020 Jun 5.

Department of Life Sciences, University of Roehampton, London, United Kingdom.

Stimulant drugs, including novel psychoactive substances (NPS, formerly "legal highs") have addictive potential which their users may not realize. Stimulants increase extracellular dopamine levels in the brain, including the reward and addiction pathways, through interacting with dopamine transporter (DAT). This work aimed to assess the molecular and atomistic mechanisms of stimulant NPS actions at DAT, which translate into biological outcomes such as dopamine release in the brain's reward pathway. We applied combined , , and methods and selected 2-diphenylmethylpiperidine (2-DPMP) as an example of stimulant NPS for this study. We measured binding of 2-DPMP to rat striatum and accumbens DAT by means of quantitative autoradiography with a selective DAT-radioligand [I]RTI-121. We evaluated the effects of intravenously administered 2-DPMP on extracellular dopamine in the accumbens-shell and striatum using microdialysis in freely moving rats. We used dynamic modeling to investigate the interactions of 2-DPMP within DAT, in comparison with cocaine and amphetamine. 2-DPMP potently displaced the radioligand in the accumbens and striatum showing dose-dependence from 0.3 to 30 μM. IC values were: 5.65 × 10M for accumbens shell and 6.21 × 10M for dorsal striatum. Dose-dependent responses were also observed in accumbens-shell and striatum , with significant increases in extracellular dopamine levels. Molecular dynamics simulations identified contrasting conformational changes of DAT for inhibitors (cocaine) and releasers (amphetamine). 2-DPMP led to molecular rearrangements toward an outward-facing DAT conformation that suggested a cocaine-type effect. The present combination of molecular modeling with experimental neurobiological procedures allows for extensive characterization of the mechanisms of drug actions at DAT as the main molecular target of stimulants, and provides an insight into the role of dopamine in the molecular and neurobiological mechanisms of brain responses to stimulant NPS that have addictive potential. Such knowledge reveals the risk of addiction related to NPS use. The research presented here can be adapted for other psychostimulants that act at their membrane protein targets.
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http://dx.doi.org/10.3389/fphar.2020.00806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289955PMC
June 2020

The fine art of preparing membrane transport proteins for biomolecular simulations: Concepts and practical considerations.

Methods 2021 01 17;185:3-14. Epub 2020 Feb 17.

Department of Life Sciences, University of Roehampton, London SW15 4JD, UK. Electronic address:

Molecular dynamics (MD) simulations have developed into an invaluable tool in bimolecular research, due to the capability of the method in capturing molecular events and structural transitions that describe the function as well as the physiochemical properties of biomolecular systems. Due to the progressive development of more efficient algorithms, expansion of the available computational resources, as well as the emergence of more advanced methodologies, the scope of computational studies has increased vastly over time. We now have access to a multitude of online databases, software packages, larger molecular systems and novel ligands due to the phenomenon of emerging novel psychoactive substances (NPS). With so many advances in the field, it is understandable that novices will no doubt find it challenging setting up a protein-ligand system even before they run their first MD simulation. These initial steps, such as homology modelling, ligand docking, parameterization, protein preparation and membrane setup have become a fundamental part of the drug discovery pipeline, and many areas of biomolecular sciences benefit from the applications provided by these technologies. However, there still remains no standard on their usage. Therefore, our aim within this review is to provide a clear overview of a variety of concepts and methodologies to consider, providing a workflow for a case study of a membrane transport protein, the full-length human dopamine transporter (hDAT) in complex with different stimulants, where MD simulations have recently been applied successfully.
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http://dx.doi.org/10.1016/j.ymeth.2020.02.009DOI Listing
January 2021

Mechanistic Insights into the Stimulant Properties of Novel Psychoactive Substances (NPS) and Their Discrimination by the Dopamine Transporter-In Silico and In Vitro Exploration of Dissociative Diarylethylamines.

Brain Sci 2018 Apr 7;8(4). Epub 2018 Apr 7.

Department of Life Sciences, University of Roehampton, London SW15 4JD, UK.

Novel psychoactive substances (NPS) may have unsuspected addiction potential through possessing stimulant properties. Stimulants normally act at the dopamine transporter (DAT) and thus increase dopamine (DA) availability in the brain, including nucleus accumbens, within the reward and addiction pathway. This paper aims to assess DAT responses to dissociative diarylethylamine NPS by means of in vitro and in silico approaches. We compared diphenidine (DPH) and 2-methoxydiphenidine (methoxphenidine, 2-MXP/MXP) for their binding to rat DAT, using autoradiography assessment of [I]RTI-121 displacement in rat striatal sections. The drugs' effects on electrically-evoked DA efflux were measured by means of fast cyclic voltammetry in rat accumbens slices. Computational modeling, molecular dynamics and alchemical free energy simulations were used to analyse the atomistic changes within DAT in response to each of the five dissociatives: DPH, 2-MXP, 3-MXP, 4-MXP and 2-Cl-DPH, and to calculate their relative binding free energy. DPH increased DA efflux as a result of its binding to DAT, whereas MXP had no significant effect on either DAT binding or evoked DA efflux. Our computational findings corroborate the above and explain the conformational responses and atomistic processes within DAT during its interactions with the dissociative NPS. We suggest DPH can have addictive liability, unlike MXP, despite the chemical similarities of these two NPS.
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http://dx.doi.org/10.3390/brainsci8040063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924399PMC
April 2018

Identification of a nucleoside analog active against adenosine kinase-expressing plasma cell malignancies.

J Clin Invest 2017 Jun 15;127(6):2066-2080. Epub 2017 May 15.

Department of Pathology and Laboratory Medicine.

Primary effusion lymphoma (PEL) is a largely incurable malignancy of B cell origin with plasmacytic differentiation. Here, we report the identification of a highly effective inhibitor of PEL. This compound, 6-ethylthioinosine (6-ETI), is a nucleoside analog with toxicity to PEL in vitro and in vivo, but not to other lymphoma cell lines tested. We developed and performed resistome analysis, an unbiased approach based on RNA sequencing of resistant subclones, to discover the molecular mechanisms of sensitivity. We found different adenosine kinase-inactivating (ADK-inactivating) alterations in all resistant clones and determined that ADK is required to phosphorylate and activate 6-ETI. Further, we observed that 6-ETI induces ATP depletion and cell death accompanied by S phase arrest and DNA damage only in ADK-expressing cells. Immunohistochemistry for ADK served as a biomarker approach to identify 6-ETI-sensitive tumors, which we documented for other lymphoid malignancies with plasmacytic features. Notably, multiple myeloma (MM) expresses high levels of ADK, and 6-ETI was toxic to MM cell lines and primary specimens and had a robust antitumor effect in a disseminated MM mouse model. Several nucleoside analogs are effective in treating leukemias and T cell lymphomas, and 6-ETI may fill this niche for the treatment of PEL, plasmablastic lymphoma, MM, and other ADK-expressing cancers.
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http://dx.doi.org/10.1172/JCI83936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451239PMC
June 2017

Combined in vitro and in silico approaches to the assessment of stimulant properties of novel psychoactive substances - The case of the benzofuran 5-MAPB.

Prog Neuropsychopharmacol Biol Psychiatry 2017 04 24;75:1-9. Epub 2016 Nov 24.

University of Roehampton, London SW15 4JD, UK. Electronic address:

Novel psychoactive substances (NPS) are increasingly prevalent world-wide although their pharmacological characteristics are largely unknown; those with stimulant properties, due to interactions with the dopamine transporter (DAT), have addictive potential which their users may not realise. We evaluated the binding of 1-(1-benzofuran-5-yl)-N-methylpropan-2-amine (5-MAPB) to rat striatal DAT by means of quantitative autoradiography with [I]RTI-121, and the effects of 5-MAPB on electrically-evoked dopamine efflux by fast-cyclic voltammetry in rat brain slices. 5-MAPB displaced [I]RTI-121 in a concentration-dependent manner, with significant effects at 10 and 30μM. The voltammetry data suggest that 5-MAPB reduces the rate of dopamine reuptake; while the peak dopamine efflux was not increased, the area under the curve was augmented. 5-MAPB can also cause reverse dopamine transport consistent with stimulant properties, more similar to amphetamine than cocaine. Molecular modelling and docking studies compared the binding site of DAT in complex with 5-MAPB to dopamine, amphetamine, 5-APB, MDMA, cocaine and RTI-121. This structural comparison reveals a binding mode for 5-MAPB found in the primary binding (S1) site, central to transmembrane domains 1, 3, 6 and 8, which overlaps with the binding modes of dopamine, cocaine and its analogues. Atomistic molecular dynamics simulations further show that, when in complex with 5-MAPB, DAT can exhibit conformational transitions that spontaneously isomerize the transporter into inward-facing state, similarly to that observed in dopamine-bound DAT. These novel insights, offered by the combination of computational methods of biophysics with neurobiological procedures, provide structural context for NPS at DAT and relate them with their functional properties at DAT as the molecular target of stimulants.
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http://dx.doi.org/10.1016/j.pnpbp.2016.11.004DOI Listing
April 2017

Spontaneous inward opening of the dopamine transporter is triggered by PIP2-regulated dynamics of the N-terminus.

ACS Chem Neurosci 2015 Nov 17;6(11):1825-37. Epub 2015 Aug 17.

Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University (WCMC) , New York, New York 10065, United States.

We present the dynamic mechanism of concerted motions in a full-length molecular model of the human dopamine transporter (hDAT), a member of the neurotransmitter/sodium symporter (NSS) family, involved in state-to-state transitions underlying function. The findings result from an analysis of unbiased atomistic molecular dynamics simulation trajectories (totaling >14 μs) of the hDAT molecule immersed in lipid membrane environments with or without phosphatidylinositol 4,5-biphosphate (PIP2) lipids. The N-terminal region of hDAT (N-term) is shown to have an essential mechanistic role in correlated rearrangements of specific structural motifs relevant to state-to-state transitions in the hDAT. The mechanism involves PIP2-mediated electrostatic interactions between the N-term and the intracellular loops of the transporter molecule. Quantitative analyses of collective motions in the trajectories reveal that these interactions correlate with the inward-opening dynamics of hDAT and are allosterically coupled to the known functional sites of the transporter. The observed large-scale motions are enabled by specific reconfiguration of the network of ionic interactions at the intracellular end of the protein. The isomerization to the inward-facing state in hDAT is accompanied by concomitant movements in the extracellular vestibule and results in the release of an Na(+) ion from the Na2 site and destabilization of the substrate dopamine in the primary substrate binding S1 site. The dynamic mechanism emerging from the findings highlights the involvement of the PIP2-regulated interactions between the N-term and the intracellular loop 4 in the functionally relevant conformational transitions that are also similar to those found to underlie state-to-state transitions in the leucine transporter (LeuT), a prototypical bacterial homologue of the NSS.
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http://dx.doi.org/10.1021/acschemneuro.5b00179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653762PMC
November 2015

Computational modeling of the N-terminus of the human dopamine transporter and its interaction with PIP2 -containing membranes.

Proteins 2015 May 25;83(5):952-69. Epub 2015 Mar 25.

Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, New York, 10065.

The dopamine transporter (DAT) is a transmembrane protein belonging to the family of neurotransmitter:sodium symporters (NSS). Members of the NSS are responsible for the clearance of neurotransmitters from the synaptic cleft, and for their translocation back into the presynaptic nerve terminal. The DAT contains long intracellular N- and C-terminal domains that are strongly implicated in the transporter function. The N-terminus (N-term), in particular, regulates the reverse transport (efflux) of the substrate through DAT. Currently, the molecular mechanisms of the efflux remain elusive in large part due to lack of structural information on the N-terminal segment. Here we report a computational model of the N-term of the human DAT (hDAT), obtained through an ab initio structure prediction, in combination with extensive atomistic molecular dynamics (MD) simulations in the context of a lipid membrane. Our analysis reveals that whereas the N-term is a highly dynamic domain, it contains secondary structure elements that remain stable in the long MD trajectories of interactions with the bilayer (totaling >2.2 μs). Combining MD simulations with continuum mean-field modeling we found that the N-term engages with lipid membranes through electrostatic interactions with the charged lipids PIP2 (phosphatidylinositol 4,5-Biphosphate) or PS (phosphatidylserine) that are present in these bilayers. We identify specific motifs along the N-term implicated in such interactions and show that differential modes of N-term/membrane association result in differential positioning of the structured segments on the membrane surface. These results will inform future structure-based studies that will elucidate the mechanistic role of the N-term in DAT function.
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http://dx.doi.org/10.1002/prot.24792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400265PMC
May 2015

ESCRT-II/Vps25 constrains digit number by endosome-mediated selective modulation of FGF-SHH signaling.

Cell Rep 2014 Oct 16;9(2):674-87. Epub 2014 Oct 16.

Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address:

Sorting and degradation of receptors and associated signaling molecules maintain homeostasis of conserved signaling pathways during cell specification and tissue development. Yet, whether machineries that sort signaling proteins act preferentially on different receptors and ligands in different contexts remains mysterious. Here, we show that Vacuolar protein sorting 25, Vps25, a component of ESCRT-II (Endosomal Sorting Complex Required for Transport II), directs preferential endosome-mediated modulation of FGF signaling in limbs. By ENU-induced mutagenesis, we isolated a polydactylous mouse line carrying a hypomorphic mutation of Vps25 (Vps25(ENU)). Unlike Vps25-null embryos we generated, Vps25(ENU/ENU) mutants survive until late gestation. Their limbs display FGF signaling enhancement and consequent hyperactivation of the FGF-SHH feedback loop causing polydactyly, whereas WNT and BMP signaling remain unperturbed. Notably, Vps25(ENU/ENU) Mouse Embryonic Fibroblasts exhibit aberrant FGFR trafficking and degradation; however, SHH signaling is unperturbed. These studies establish that the ESCRT-II machinery selectively limits FGF signaling in vertebrate skeletal patterning.
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http://dx.doi.org/10.1016/j.celrep.2014.09.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223648PMC
October 2014

Missense dopamine transporter mutations associate with adult parkinsonism and ADHD.

J Clin Invest 2014 Jul 9;124(7):3107-20. Epub 2014 Jun 9.

Parkinsonism and attention deficit hyperactivity disorder (ADHD) are widespread brain disorders that involve disturbances of dopaminergic signaling. The sodium-coupled dopamine transporter (DAT) controls dopamine homeostasis, but its contribution to disease remains poorly understood. Here, we analyzed a cohort of patients with atypical movement disorder and identified 2 DAT coding variants, DAT-Ile312Phe and a presumed de novo mutant DAT-Asp421Asn, in an adult male with early-onset parkinsonism and ADHD. According to DAT single-photon emission computed tomography (DAT-SPECT) scans and a fluoro-deoxy-glucose-PET/MRI (FDG-PET/MRI) scan, the patient suffered from progressive dopaminergic neurodegeneration. In heterologous cells, both DAT variants exhibited markedly reduced dopamine uptake capacity but preserved membrane targeting, consistent with impaired catalytic activity. Computational simulations and uptake experiments suggested that the disrupted function of the DAT-Asp421Asn mutant is the result of compromised sodium binding, in agreement with Asp421 coordinating sodium at the second sodium site. For DAT-Asp421Asn, substrate efflux experiments revealed a constitutive, anomalous efflux of dopamine, and electrophysiological analyses identified a large cation leak that might further perturb dopaminergic neurotransmission. Our results link specific DAT missense mutations to neurodegenerative early-onset parkinsonism. Moreover, the neuropsychiatric comorbidity provides additional support for the idea that DAT missense mutations are an ADHD risk factor and suggests that complex DAT genotype and phenotype correlations contribute to different dopaminergic pathologies.
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http://dx.doi.org/10.1172/JCI73778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4071392PMC
July 2014

Quantifying water-mediated protein-ligand interactions in a glutamate receptor: a DFT study.

J Phys Chem B 2011 Jun 5;115(21):7085-96. Epub 2011 May 5.

Structural Bioinformatics and Computational Biochemistry, University of Oxford, Oxford, United Kingdom.

It is becoming increasingly clear that careful treatment of water molecules in ligand-protein interactions is required in many cases if the correct binding pose is to be identified in molecular docking. Water can form complex bridging networks and can play a critical role in dictating the binding mode of ligands. A particularly striking example of this can be found in the ionotropic glutamate receptors. Despite possessing similar chemical moieties, crystal structures of glutamate and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) in complex with the ligand-binding core of the GluA2 ionotropic glutamate receptor revealed, contrary to all expectation, two distinct modes of binding. The difference appears to be related to the position of water molecules within the binding pocket. However, it is unclear exactly what governs the preference for water molecules to occupy a particular site in any one binding mode. In this work we use density functional theory (DFT) calculations to investigate the interaction energies and polarization effects of the various components of the binding pocket. Our results show (i) the energetics of a key water molecule are more favorable for the site found in the glutamate-bound mode compared to the alternative site observed in the AMPA-bound mode, (ii) polarization effects are important for glutamate but less so for AMPA, (iii) ligand-system interaction energies alone can predict the correct binding mode for glutamate, but for AMPA alternative modes of binding have similar interaction energies, and (iv) the internal energy is a significant factor for AMPA but not for glutamate. We discuss the results within the broader context of rational drug-design.
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http://dx.doi.org/10.1021/jp200776tDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102440PMC
June 2011

A comparative analysis of the role of water in the binding pockets of ionotropic glutamate receptors.

Phys Chem Chem Phys 2010 Nov 20;12(42):14057-66. Epub 2010 Sep 20.

Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.

The binding pockets within proteins often contain water molecules. The ligand-binding core of ionotropic glutamate receptors represents an example where the binding pocket has many crystallographically reported waters, but the precise role remains unclear. It is also unclear to what extent the dynamic properties of these waters are conserved across the different receptor subtypes. In order to shed some light on these aspects we have performed multiple molecular dynamics simulations of the ligand binding core of four glutamate bound iGluR structures (GluA2, GluK1, GluK2, and GluN2A) and one apo structure (GluA2). We find that the water positions are reproduced from the simulations, but they also reveal that all but one water molecule in the binding site can be rearranged or replaced with water molecules from the bulk that enter the binding site through transient water channels. This one exception is not reported in the apo crystal structure but within 15 ns of simulation, a water molecule enters the site from the bulk suggesting that it is a favoured position regardless of the state of the protein. Further calculations demonstrate that whilst it is not needed in order to be able to predict the correct binding pose, it does contribute a large favourable interaction energy. We also find that one conserved water has a much stronger interaction with the protein in GluA2, GluK1 and GluK2 compared to the GluN2A receptor. The position of this water molecule is such that it can influence the dynamics of the proposed switch in the GluA2 and GluK1/2 receptors.
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http://dx.doi.org/10.1039/c004336bDOI Listing
November 2010

Quantifying the intrinsic effects of two point mutation models of pro-pro-pro triamino acid diamide. A first-principle computational study.

J Phys Chem B 2007 Nov 20;111(45):13135-42. Epub 2007 Oct 20.

Ontario Cancer Institute, Division of Cancer Genomics and Proteomics, MaRS Center, Toronto Medical Discovery Tower, Toronto, Ontario M5G 1L7, Canada.

Stabilities and conformational properties of two Pro --> Thr point mutation models were computed at the B3LYP/6-31G(d) level of theory for the parent triamino acid diamide Pro-Pro-Pro (HCO-Pro-Pro-Pro-NH2). Geometrical parameters for the amino acid sequences, used in the molecular orbital computations for Pro-Pro-Thr and Pro-Thr-Pro, were retrieved from the Protein Data Bank. Thermodynamic functions (S, H, G) were computed for the fully optimized geometries. To assess the stabilization energetics of these mutant models, relative to the parent Pro-Pro-Pro reference conformer epsilon(L) epsilon(L) gamma(L), isodesmic reactions were constructed to calculate DeltaS, DeltaH, and DeltaG. The importance of intramolecular hydrogen bonds involving the -OH group of the Thr side chain, which emerged after the point mutations, was also examined to determine the internal stabilization of these peptide models. This study describes an approach to analyzing a point mutation at the center of a peptide chain and compares its stability to that of a point mutation at a terminal end in a small peptide model.
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http://dx.doi.org/10.1021/jp074046rDOI Listing
November 2007

Quantifying the intrinsic effects of two point mutation models of proline-proline diamino acid diamide: a first-principle computational study.

J Phys Chem B 2007 Oct 8;111(39):11592-602. Epub 2007 Sep 8.

Ontario Cancer Institute, Division of Cancer Genomics and Proteomics, MaRS Center, Toronto Medical Discovery Tower, 101 College Street, Room 5-359, Toronto, Ontario, M5G 1L7, Canada.

Two sites of a Pro-Pro diamide were subjected to individual Pro --> Thr point mutations. The parent diamide Pro-Pro as well as selected conformers of the Pro-Thr and Thr-Pro mutant models were subjected to molecular computations at the B3LYP/6-31G(d) level of theory. At the optimized geometries, thermodynamic functions (S, H, and G) were computed. In order to assess relative stabilities of the mutant models, isodesmic reactions were constructed to calculate DeltaS, DeltaH, and DeltaG, relative to the initial Pro-Pro state. The importance of intramolecular hydrogen bonds, involving the -OH group of the Thr side chain, which emerged after the point mutations were also examined. Our findings suggest a novel approach to analyzing the stability of point mutants in peptide models through the analysis of thermodynamic functions.
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http://dx.doi.org/10.1021/jp073471hDOI Listing
October 2007

Transition state infrared spectra for the trans-->cis isomerization of a simple peptide model.

J Phys Chem A 2007 Aug 9;111(34):8384-9. Epub 2007 Aug 9.

Department of Medical Biophysics, University of Toronto, Toronto Medical Discovery Tower, 101 College Street, Room 5-359, Toronto, Ontario, Canada M5G 1L7.

Trans-->cis isomerization of N-methylacetylamide (MeCO-NHMe) has been studied at the G3MP2B3 level of theory and the vibration spectrum has been calculated as a function of the torsional mode of motion along the peptide bond. Noticeable spectral differences have been observed for the transition state interconnecting the cis and trans isomers.
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http://dx.doi.org/10.1021/jp074991fDOI Listing
August 2007

First-principle computational study on the full conformational space of L-threonine diamide, the energetic stability of cis and trans isomers.

J Phys Chem A 2006 Oct;110(40):11527-36

Department of Medical Biophysics, University of Toronto, Toronto Medical Discovery Tower, 101 College Street, Room 5-359, Toronto, Ontario, Canada M5G 1L7.

First-principle computations were carried out on the conformational space of trans and cis peptide bond isomers of HCO-Thr-NH2. Using the concept of multidimensional conformational analysis (MDCA), geometry optimizations were performed at the B3LYP/6-31G(d) level of theory, and single-point energies as well as thermodynamic functions were calculated at the G3MP2B3 level of theory for the corresponding optimized structures. Two backbone Ramachandran-type potential energy surfaces (PESs) were computed, one each for the cis and trans isomers, keeping the side chain at the fully extended orientation (chi1=chi2=anti). Similarly, two side chain PESs for the cis and trans isomers were generated for the (phi=psi=anti) orientation corresponding to approximately the betaL backbone conformation. Besides correlating the relative Gibbs free energy of the various stable conformations with the number of stabilizing hydrogen bonds, the process of trans-->cis isomerization is discussed in terms of intrinsic stabilities as measured by the computed thermodynamic functions.
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http://dx.doi.org/10.1021/jp0680488DOI Listing
October 2006

First principle computational study on the full conformational space of L-proline diamides.

J Phys Chem A 2005 Mar;109(11):2660-79

Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9.

Ab initio molecular orbital computations were carried out at three levels of theory: RHF/3-21G, RHF/6-31G(d), and B3LYP/6-31G(d), on four model systems of the amino acid proline, HCO-Pro-NH2 [I], HCO-Pro-NH-Me [II], MeCO-Pro-NH2 [III], and MeCO-Pro-NH-Me [IV], representing a systematic variation in the protecting N- and C-terminal groups. Three previously located backbone conformations, gammaL, epsilonL, and alphaL, were characterized together with two ring-puckered forms syn (gauche+ = g+) or "DOWN" and anti (gauche- = g-) or "UP", as well as trans-trans, trans-cis, cis-trans, and cis-cis peptide bond isomers. The topologies of the conformational potential energy cross-sections (PECS) of the potential energy hypersurfaces (PEHS) for compounds [I]-[IV] were explored and analyzed in terms of potential energy curves (PEC), and HCO-Pro-NH2 [I] was also analyzed in terms of potential energy surfaces (PESs). Thermodynamic functions were also calculated for HCO-Pro-NH2 [I] at the CBS-4M and G3MP2 levels of theory. The study confirms that the use of the simplest model, compound [I] with P(N) = P(C) = H, along with the RHF/3-21G level of theory, is an acceptable practice for the analysis of peptide models because only minor differences in geometry and stability are observed.
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http://dx.doi.org/10.1021/jp040594iDOI Listing
March 2005