Computational Chemistry and Macromolecular Modeling

National Institute Of Environmental Health Sciences

Investigators

Linked publications, trials & patents

Abstract

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) 1. Modeling and structural characterization of DNA and RNA G-quadruplexes in the studies involving the mechanisms by which nucleic acid sequences and structures signal to pause RNA polymerase (Jason Watts (ERBL/DIR)) 2. Structural characterization of mutations in proteins Titin, Obscurin, and Nebulin in the study of “Cumulative burden of genes involved in muscle function and regeneration and antibody specific MHC haplotypes determine genetic architecture of early-onset juvenile dermatomyositis.” (Lisa Rider (CRB/DIR) and Raphaela Goldback-Mansky (LCIM at NIAID)) 3. Computational energy analysis and structural characterization of the herpes simplex virus-1 helicase-primase complex. (Scott Williams (GISBL/DIR)) 4. Modeling Alpha-7 pentamer interactions with small peptides (a 12-mer and a 17-mer) resembling the furin cleavage region of SARS-Cov-2. (Jerry Yakel (NL/DIR)) 5. Assisting with Cryo-EM structure refinements when there are multiple structural domains with various conformational samples available from the experimental structures at a very low resolution (Mario Borgnia (GISBL/DIR) and Bob Ross (NCSU)) 6. Molecular docking and dynamic characterizations of nuclear receptor NURR1 which is an important transcriptional regulator in the maintenance and differentiation of mdDA neurons during development, interactions with Vitamin D3 metabolites (Anton Jetten (IIDL/DIR)) 7. Modeling lipid- allergen protein interactions and protein-protein interactions in allergen proteins (Geoff Mueller (GISBL/DIR)) 8. Modeling dynamics of Synuclein-1 and -2 multimers in the presence of membrane bilayers (Charly Guardia (RDBL/DIR)) 9. Molecular dynamics simulations of MD of the N-terminal proline rich domain of Orai1, a calcium channel protein crucial for store-operated calcium entry in cells. (Anant Parekh (MCBL/DIR)) 10. Molecular dynamic simulations on various patient mutations found in NVL2, a large AAA-ATPase that is active as a homo-hexamer in the ribosome assembly (Robin Stanly (MCB/DIR)) 11. Molecular dynamics of CCA adding enzymes CCA1 and CCA2 from S. pombe in transfer RNA synthesis (Traci Hall (ERBL/DIR)) 12. Structure-function analysis of a novel E. coli dGTPase with both fidelity and antiviral functions using molecular dynamics simulations (Roel Schaaper (GISBL/DIR)) 13. Quantum mechanical characterization of nitro-polyaromatic hydrocarbons to determine they should be listed in the Report on Carcinogens (Ruth Lunn (DTT)) 14. Molecular dynamic simulations of drug resistance mutations in Gyr A of Pseudomonas aeruginosa (Paul Doetsch (GISBL/DIR)) 15. Glucocorticoid receptor (GR)/ mineralocorticoid receptor (MR), MR/MR, GR/GR dimer simulations and mutation analysis in the studies of their involvement in the signal transduction (John Cidlowaski (MCBL/DIR)) 16. Small molecule characterization using quantum chemistry for Metabolomics research (Alan Jarmusch (IIDL/DIR)) 17. Characterization of missense variants in tumor necrosis factor receptor superfamily member 3 (LTBR) found in a patient with immunodeficiency. (Michail Lionakis (LCIM/DIR/NIAID)) 18. TENT5C interactions with glucocorticoid and estrogen receptors (Marcos Morgan (RDBL/DIR)) 19. Modeling and small molecule docking on PMS1to alter DNA bending to study mismatch repair and the cause of Huntington’s disease (Karen Usdin (LCMB/DIR/NIDDK)). 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.