Publications by authors named "Matthew R Hennefarth"

8 Publications

  • Page 1 of 1

Mineralized Peyronie's plaque has a phenotypic resemblance to bone.

Acta Biomater 2021 Nov 21. Epub 2021 Nov 21.

Division of Biomaterials and Bioengineering, Department of Preventative and Restorative Dental Sciences, School of Dentistry, University of California San Francisco, California, United States of America; Department of Urology, School of Medicine, University of California, San Francisco, California, United States of America. Electronic address:

Mineralized Peyronie's plaque (MPP) impairs penile function. The association, colocalization, and dynamic interplay between organic and inorganic constituents can provide insights into biomineralization of Peyronie's plaque. Human MPPs (n = 11) were surgically excised, and the organic and inorganic constituents were spatially mapped using multiple high-resolution imaging techniques. Multiscale image analyses resulted in spatial colocalization of elements within a highly porous material with heterogenous composition, lamellae, and osteocytic lacuna-like features with a morphological resemblance to bone. The lower (520 ±179 mg/cc) and higher (1024 ± 155 mg/cc) mineral density regions were associated with higher (11%) and lower (7%) porosities in MPP. Energy dispersive X-ray and micro-X-ray fluorescent spectroscopic maps in the higher mineral density regions of MPP revealed higher counts of calcium (Ca) and phosphorus (P), and a Ca/P ratio of 1.48 ± 0.06 similar to bone. More importantly, higher counts of zinc (Zn) were localized at the interface between softer (more organic to inorganic ratio) and harder (less organic to inorganic ratio) tissue regions of MPP and adjacent softer matrix, indicating the involvement of Zn-related proteins and/or pathways in the formation of MPP. In particular, dentin matrix protein-1 (DMP-1) was colocalized in a matrix rich in proteoglycans and collagen that contained osteocytic lacuna-like features. This combined materials science and biochemical with correlative microspectroscopic approach provided insights into the plausible cellular and biochemical pathways that incite mineralization of an existing fibrous Peyronie's plaque. STATEMENT OF SIGNIFICANCE: Aberrant human penile mineralization is known as mineralized Peyronie's plaque (MPP) and often results in a loss of form and function. This study focuses on investigating the spatial association of matrix proteins and elemental composition of MPP by colocalizing calcium, phosphorus, and trace metal zinc with dentin matrix protein 1 (DMP-1), acidic proteoglycans, and fibrillar collagen along with the cellular components using high resolution correlative microspectroscopic techniques. Spatial maps provided insights into cellular and biochemical pathways that incite mineralization of fibrous Peyronie's plaque in humans.
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http://dx.doi.org/10.1016/j.actbio.2021.11.025DOI Listing
November 2021

Machine Learning to Predict Diels-Alder Reaction Barriers from the Reactant State Electron Density.

J Chem Theory Comput 2021 Oct 3;17(10):6203-6213. Epub 2021 Sep 3.

Department of Chemistry and Biochemistry, University of California, Los Angeles, 607 Charles E. Young Drive East, Los Angeles, California 90095-1569, United States.

Reaction barriers are key to our understanding of chemical reactivity and catalysis. Certain reactions are so seminal in chemistry that countless variants, with or without catalysts, have been studied, and their barriers have been computed or measured experimentally. This wealth of data represents a perfect opportunity to leverage machine learning models, which could quickly predict barriers without explicit calculations or measurement. Here, we show that the topological descriptors of the quantum mechanical charge density in the reactant state constitute a set that is both rigorous and continuous and can be used effectively for the prediction of reaction barrier energies to a high degree of accuracy. We demonstrate this on the Diels-Alder reaction, highly important in biology and medicinal chemistry, and as such, studied extensively. This reaction exhibits a range of barriers as large as 270 kJ/mol. While we trained our single-objective supervised (labeled) regression algorithms on simpler Diels-Alder reactions in solution, they predict reaction barriers also in significantly more complicated contexts, such a Diels-Alder reaction catalyzed by an artificial enzyme and its evolved variants, in agreement with experimental changes in . We expect this tool to apply broadly to a variety of reactions in solution or in the presence of a catalyst, for screening and circumventing heavily involved computations or experiments.
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http://dx.doi.org/10.1021/acs.jctc.1c00623DOI Listing
October 2021

Advances in optimizing enzyme electrostatic preorganization.

Curr Opin Struct Biol 2021 Jul 16;72:1-8. Epub 2021 Jul 16.

Department of Chemistry and Biochemistry, University of California, Los Angeles, 607 Charles E. Young Drive East, Los Angeles, CA 90095-1569, USA; California NanoSystems Institute, University of California, Los Angeles, 570 Westwood Plaza, Los Angeles, CA 90095-1569, USA. Electronic address:

Utilizing electric fields to catalyze chemical reactions is not a new idea, but in enzymology it undergoes a renaissance, inspired by Warhsel's concept of electrostatic preorganization. According to this concept, the source of the immense catalytic efficiency of enzymes is the intramolecular electric field that permanently favors the reaction transition state over the reactants. Within enzyme design, computational efforts have fallen short in designing enzymes with natural-like efficacy. The outcome could improve if long-range electrostatics (often omitted in current protocols) would be optimized. Here, we highlight the major developments in methods for analyzing and designing electric fields generated by the protein scaffolds, in order to both better understand how natural enzymes function, and aid artificial enzyme design.
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http://dx.doi.org/10.1016/j.sbi.2021.06.006DOI Listing
July 2021

Corrigendum to "Physicochemical and biochemical spatiotemporal maps of a mouse penis". [J. Biomech. 101 (2020) 109637].

J Biomech 2021 Aug 25;125:110563. Epub 2021 Jun 25.

Division of Biomaterials and Bioengineering, Department of Preventive and Restorative Dental Sciences, School of Dentistry, University of California San Francisco, San Francisco, CA, United States; Department of Urology, School of Medicine, University of California San Francisco, San Francisco, CA, United States. Electronic address:

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http://dx.doi.org/10.1016/j.jbiomech.2021.110563DOI Listing
August 2021

Heterogeneous Intramolecular Electric Field as a Descriptor of Diels-Alder Reactivity.

J Phys Chem A 2021 Feb 1;125(5):1289-1298. Epub 2021 Feb 1.

Department of Chemistry and Biochemistry, University of California, Los Angeles, 607 Charles E. Young Drive East, Los Angeles, California 90095-1569, United States.

External electric fields have proven to be an effective tool in catalysis, on par with pressure and temperature, affecting the thermodynamics and kinetics of a reaction. However, fields in molecules are complicated heterogeneous vector objects, and there is no universal recipe for grasping the exact features of these fields that implicate reactivity. Herein, we demonstrate that topological features of the heterogeneous electric field within the reactant state and of the quantum mechanical electron density-a scalar reporter on the field experienced by the system-can be identified as rigorous descriptors of the reactivity to follow. We scrutinize specifically the Diels-Alder reaction. Its 3D nature and the lack of a singular directionality of charge movement upon barrier crossing make the effect of the electric field not obvious. We show that the electric field topology around the dienophile double bond and the associated changes in the topology of the electron density in this bond are predictors of the reaction barrier. They are also the metrics to rationalize and predict how the external field would inhibit or enhance the reaction. The findings pave the way toward designing external fields for catalysis and reading the reactivity without an explicit mechanistic interrogation, for a variety of reactions.
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http://dx.doi.org/10.1021/acs.jpca.1c00181DOI Listing
February 2021

Physicochemical and biochemical spatiotemporal maps of a mouse penis.

J Biomech 2020 03 16;101:109637. Epub 2020 Jan 16.

Division of Biomaterials and Bioengineering, Department of Preventive and Restorative Dental Sciences, School of Dentistry, University of California San Francisco, San Francisco, CA, United States; Department of Urology, School of Medicine, University of California San Francisco, San Francisco, CA, United States. Electronic address:

Spatiotemporal mechanobiology resulting in penile pathologies continues to be investigated using small scale animals models such as mice. However, species-dependent functional biomechanics of a mouse penis, is not known. In this study, spatial mapping of a mechanosensitive transcription factor, scleraxis (Scx), at ages 4, 5, 6 weeks, and 1 year were generated to identify mechanoactive regions within penile tissues. Reconstructed volumes of baculum collected using micro X-ray computed tomography illustrated significantly increased baculum length with decreased porosity, and increased mineral density (p < 0.05) with age. The bony-baculum was held centrally in the Scx positive corpus cavernosum glandis (CCG), indicating mechanoactivity within the struts in a 6 week old mouse. The struts also were stained positive for fibrillar proteins including collagen and elastin, and globular proteins including protein gene product 9.5, and α-smooth muscle actin. The corpus cavernosum penis (CCP) contained significantly (p < 0.05) more collagen than CCG within the same penis, and both regions contained blood vessels with equivalent innervation at any given age. Comparison of volumes of flaccid and erect penile forms revealed functional characteristics of the CCP. Results of this study provided insights into biomechanical function of the CCG; in that, it is a high-pressure chamber that stiffens the penis and is similar to the human corpus cavernosum.
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http://dx.doi.org/10.1016/j.jbiomech.2020.109637DOI Listing
March 2020

The Case for Enzymatic Competitive Metal Affinity Methods.

ACS Catal 2020 Feb 17;10(3):2298-2307. Epub 2020 Jan 17.

Department of Chemistry and Biochemistry, University of California, Los Angeles, 607 Charles E. Young Drive East, Los Angeles, CA 90095-1569, USA.

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http://dx.doi.org/10.1021/acscatal.9b04831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130888PMC
February 2020

A Chemical Biology Approach to Model Pontocerebellar Hypoplasia Type 1B (PCH1B).

ACS Chem Biol 2018 10 6;13(10):3000-3010. Epub 2018 Sep 6.

Department of Pharmacology , College of Medicine, University of Arizona , Tucson , Arizona 85724 , United States.

Mutations of EXOSC3 have been linked to the rare neurological disorder known as Pontocerebellar Hypoplasia type 1B (PCH1B). EXOSC3 is one of three putative RNA-binding structural cap proteins that guide RNA into the RNA exosome, the cellular machinery that degrades RNA. Using RNAcompete, we identified a G-rich RNA motif binding to EXOSC3. Surface plasmon resonance (SPR) and microscale thermophoresis (MST) indicated an affinity in the low micromolar range of EXOSC3 for long and short G-rich RNA sequences. Although several PCH1B-causing mutations in EXOSC3 did not engage a specific RNA motif as shown by RNAcompete, they exhibited lower binding affinity to G-rich RNA as demonstrated by MST. To test the hypothesis that modification of the RNA-protein interface in EXOSC3 mutants may be phenocopied by small molecules, we performed an in-silico screen of 50 000 small molecules and used enzyme-linked immunosorbant assays (ELISAs) and MST to assess the ability of the molecules to inhibit RNA-binding by EXOSC3. We identified a small molecule, EXOSC3-RNA disrupting (ERD) compound 3 (ERD03), which ( i) bound specifically to EXOSC3 in saturation transfer difference nuclear magnetic resonance (STD-NMR), ( ii) disrupted the EXOSC3-RNA interaction in a concentration-dependent manner, and ( iii) produced a PCH1B-like phenotype with a 50% reduction in the cerebellum and an abnormally curved spine in zebrafish embryos. This compound also induced modification of zebrafish RNA expression levels similar to that observed with a morpholino against EXOSC3. To our knowledge, this is the first example of a small molecule obtained by rational design that models the abnormal developmental effects of a neurodegenerative disease in a whole organism.
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http://dx.doi.org/10.1021/acschembio.8b00745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504997PMC
October 2018
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