Computational Chemistry and Macromolecular Modeling

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Principal Investigator: William  Copeland
Organization: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
Fiscal Year: 2024
Award: $470,939
Funding agency: National Institute of Environmental Health Sciences

During this fiscal year we continued to devote major effort to work aimed at applications of molecular dynamics and quantum mechanics/molecular mechanics simulations required to help support the computational chemistry and molecular modeling needs of NIEHS scientists.  Some projects involved creation of solution structures of peptides and proteins using state-of-the-art molecular dynamics simulations and the others involved a careful look at the reactive dynamics at or near the active site of the biological systems of interest. Several docking studies and energy characterization studies are highlights of our efforts.
Most computational chemistry and molecular modeling tools that have been utilized in the present research efforts are either developed by us or modified by us. Almost all tools used in the analysis of molecular dynamics trajectories required to obtain predicted solution structures and in the energy decomposition schemes of quantum mechanics/molecular mechanics (QMMM) calculations are also written by us. The current list of projects includes (but not limited to) double strand break repair;  QM/MM/MD calculations of dRP lyase; solution structure evaluations of Tristetraproline (a protein involved in RNA degradation) of various species that affects RNA binding; Phosphopeptide interactions of the Nbs1 N-terminal FHA-BRCT1/2 domains;  modeling of DNA polymerase activity with the inclusion of some modified-ribonucleotides (and modified pyrophosphates in the case of the reverse reaction) at both classical and QMMM level; DNA and RNA dynamics in the presence of various peptides and proteins;  juvenile dermatomyositis and the muscle structural protein mutations; interactions of lipids with CYP2J2 proteins; binding of various small molecules such as BPA and its derivatives on estrogen receptor, its mutants and androgen receptor, Characterization of TENT5C interactions with ER; GR/MR dimerization; quantum mechanical characterization of small drug-like molecules;  role of various metal ions in nucleotide insertion during DNA polymerase action; modeling dGTP Triphosphohydrolase; Small molecule docking onto various proteins; damaged DNA structure characterizations using molecular dynamics simulations; Structural and ligand binding analysis of the pet allergens Can f1 and Fel d; HSD17B13 structure model validation and the HSD17B13-lipid models; structure function of intronic splice AIRE variant associated with APECED syndrome; Alpha7 binding with SARS-Cov2 spike peptide.
In addition, as a measure for efficient spending and also as a precautionary measure to carry out our functions under constraints of budgetary restrictions, we have been continuing to explore the idea of testing and setting up computer servers based on low cost, off-the-shelf components and GPUs to efficiently run MD simulations that require heavy utilization of multiple processors to sample systems with millions of atoms and to complete QMMM calculations that demand access to a large sum of memory at a given instance due to inherent complexity of the calculations.

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