Laboratory of
Computational Biochemistry

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Tuesday, August 19th:

COMP Poster session

Jim Keener (Undergraduate student at the University of Pittsburgh) presented his work (COMP-206):
Developing semiempirical molecular orbital (SMO) parameters to accurately simulate HPC-Dehydrogenase enzymatic reactions.

View the poster PDF ( 1.6MB )

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Wednesday, August 20th:

Troy Wymore and Charles L. Brooks (University of Michigan) organized a symposium on “Combining Computational Chemistry and Sequence-based Bioinformatics for Structure-Function-Activity Relationships” held in the Division of Computers in Chemistry.

The first session included presentations from Zaida Luthey-Schulten (University of Illinois @ Urbana-Champaign), Jacquelyn S. Fetrow (Wake Forest), Ruth Nussinov (National Cancer Institute), Allison Langham (University of Minnesota) and Pratul K. Agarawal (Oak Ridge National Laboratory).

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Troy Wymore presented in the Inorganic Division a talk on:

Structure-function relationships of the Gln64His Hemoglobin I mutant from Lucina pectinata determined through MM and QM/MM simulations.

Authors: Troy Wymore, Hector Arbelo, Shawn T. Brown and Juan Lopez-Garriga
National Resource for Biomedical Supercomputing, Pittsburgh Supercomputing Center
University of Puerto Rico Mayaguez

Abstract:

We will describe our research into the structure and function of the Gln64His Hemoglobin I (HbI) mutant from Lucina pectinata. This protein can form sulf-hemoglobin presumably by first reacting with hydrogen peroxide. Yet, this protein seemingly lacks residues in the active site that may stabilize key intermediates and transition states that convert hydrogen peroxide to water as the protein evolves from the Fe(III) to Fe(IV) oxidation state. Therefore, we performed molecular dynamics (MD) simulations in excess of 10 nanoseconds using the CHARMM force field that was modified to better describe the heme system bound to hydrogen peroxide. These simulations, so far, have not shown the penetration of water molecules into the active site that might assist in the conversion of hydrogen peroxide to water. Instead, various active-site aromatic residues that are properly aligned may serve this function. Finally, the structures and energetic profiles for intermediates and transition states for the reaction of the mutant HbI with hydrogen peroxide calculated using the hybrid B3LYP/LANL2DZ//CHARMM potential energy function will be presented.

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Thursday, August 21st:

Troy Wymore presented in the symposium "Combining Computational Chemistry and Sequence-based Bioinformatics for Structure-Function-Activity Relationships" his work:

Group Entropy analysis and hybrid Quantum Mechanical/Molecular Mechanical simulations for elucidation of enzyme function

Authors: Troy Wymore, Hugh B. Nicholas Jr. and John Hempel
Pittsburgh Supercomputing Center, University of Pittsburgh

Abstract:

We will describe our research that has lead to a successful integration of sequence-based bioinformatics and atomic scale simulation on the Aldehyde Dehydrogenase (ALDH) family. This integration has resulted in compelling hypotheses concerning the molecular basis for two metabolic diseases as well as a novel enzyme mechanism. We developed and applied analyses that identify residues in biological macromolecules that confer specificity of interaction on the members of a paralogous family of molecules. The analysis uses the Kullback-Leibler (KL) distance; an information theory measure of entropy. Residues that have a high KL distance represent positions in the alignment where there are large systematic differences in the kinds of residues present in the two subfamilies (i.e., the defined subfamily under investigation and the rest of the alignment). We also sought to better understand how these residues impact on the ALDH chemical mechanism. Therefore, we employed molecular dynamics (MD) simulation methods using both Molecular Mechanical (MM) potentials for studies of substrate binding and hybrid Quantum Mechanical (QM)/MM potentials for the subsequent reactions. The results suggest that the intermediate formed upon nucleophilic attack of the enzyme on the substrate is stabilized by a proton transfer from a main chain amide. This proton transfer is supported by interactions with a residue having high group entropy. Mutating residues that disrupt this “second sphere” interaction could be the molecular basis behind two metabolic diseases.