Computational Chemistry and Macromolecular Modeling

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Principal Investigator: William  Copeland
Organization: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
Fiscal Year: 2022
Award: $461,744
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 dynamics in the presence of carcinogenic dye molecules;  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; quantum mechanical characterization of small drug-like molecules;  role of various metal ions in nucleotide insertion during DNA polymerase action; modeling dGTP Triphosphohydrolase; modeling novel mutations in mitochondrial single-strand binding protein; Small molecule docking onto various proteins; damaged DNA structure characterizations using molecular dynamics simulations.
In addition, several proteins related to Covid-19 were  modeled to be used in various research activities. These research activities include modeling Spike-protein trimer; interactions of hyluronic acid with the spike protein; interactions of spike protein with nicotinamide acetylcholine receptor; structure evaluation of SARS-CoV-2 Endoribonuclease Nsp15; Zinc binding to Covid-19 cyctein proteases and the RNA-dependent RNA-polymerase; small molecule interactions with Mpro and structure characterization of SARS-COV-2 main protease domain with respective to its residue protonation states at the active site.
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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