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Principal Investigator: William Copeland
Organization: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
Fiscal Year: 2021
Award: $453,829
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; Topoisomerase-2 reaction dynamics, 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; reversal of drug resistance by small molecules ABCB1 and ABCG2 expressing multidrug resistant tumor cells; role of various metal ions in nucleotide insertion during DNA polymerase action; modeling dGTP Triphosphohydrolase; hydrophobic lipid interactions with allergen proteins such as Bla g1 and Ara h; modeling novel mutations in mitochondrial single-strand binding protein; Small molecule docking onto PUF family 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.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><3-Pyridinecarboxamide><5'-deoxyribose phosphate lyase><ABC15><ABC20><ABCB1><ABCB1 gene><ABCG2><ABCG2 gene><ABCP><ACh Receptors><ATP-Binding Cassette, Sub-Family G (WHITE), Member 2 Gene><ATP-Binding Cassette, Sub-Family G, Member 2><ATP-Binding Cassette, Subfamily G, Member 2><Acetylcholine Receptors><Acids><Active Sites><Affect><Allergens><Androgen Receptor><Area><Attention><BCRP><BCRP1><Binding><Binding Proteins><Biological><Breast Cancer Resistance Protein><COVID-19><COVID-19 virus><COVID19><COVID19 virus><CV-19><CV19><CYP2J2><CYP2J2 gene><Cholinergic Receptors><Cholinoceptive Sites><Cholinoceptors><Classical Mechanics><CoV-2><CoV2><Coloring Agents><Computers><Cytochrome P450 Arachidonic Acid Epoxygenase><Cytochrome P450, Subfamily IIJ, Polypeptide 2><DNA><DNA Damage><DNA Injury><DNA Polymerases><DNA Structure><DNA-Dependent DNA Polymerases><DNA-Directed DNA Polymerase><Deoxyribonucleic Acid><Dermatomyositis><Dermatopolymyositis><Diphosphates><Docking><Double Strand Break Repair><Drug resistance><Drugs><Dyes><EC 2.7.7.48><EST157481><Endoribonucleases><Esteroproteases><Estrogen Receptors><Evaluation><FHA><GP170><Genetic Alteration><Genetic Change><Genetic defect><Goals><Health><Human><Hydrophobicity><Investigators><Ions><Juvenile Dermatomyositis><Ligand Binding Protein><Ligand Binding Protein Gene><Lipids><MDR-1><MDR1><MDR1 Protein><MRX><MXR1><Measures><Mechanics><Medication><Memory><Metals><Methodology><Methods><Mitochondria><Mitoxantrone Resistance Protein><Modeling><Modern Man><Molecular Analysis><Molecular Configuration><Molecular Conformation><Molecular Dynamics Simulation><Molecular Interaction><Molecular Modeling Nucleic Acid Biochemistry><Molecular Modeling Protein/Amino Acid Biochemistry><Molecular Models><Molecular Stereochemistry><Multi-Drug Resistance><Multidrug Resistance><Multidrug Resistance 1><Multidrug Resistance Gene-1><Multidrug Resistance Gene-1s><Multidrug Resistance Proteins><Multidrug Resistant Proteins><Multiple Drug Resistance><Multiple Drug Resistant><Mutation><N-terminal><NH2-terminal><NIEHS><National Institute of Environmental Health Sciences><Niacinamide><Nicotinamide><Nicotinamidum><Nicotinic acid amide><Nicotylamide><Nucleotides><P-GP><P-Glycoprotein><P-Glycoprotein 1 Gene><PGY-1 Protein><PGY1><Pellagra-Preventing Factor><Peptidases><Peptide Hydrolases><Pharmaceutic Preparations><Pharmaceutical Preparations><Phosphopeptides><Placenta-Specific ATP-Binding Cassette Transporter><Polymyositis-Dermatomyositis><Procedures><Process><Protease Domain><Protease Gene><Proteases><Protein Binding><Protein Family><Proteinases><Proteins><Proteolytic Domain><Proteolytic Enzymes><Pyrophosphates><Quantum Mechanics><RNA Binding><RNA Degradation><RNA Replicase><RNA bound><RNA endonuclease><RNA-Dependent RNA Polymerase><RNA-Directed RNA Polymerase><Reaction><Research><Research Activity><Research Personnel><Researchers><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistant to Multiple Drug><Resistant to multi-drug><Resistant to multidrug><Resort><Ribonucleoside Phosphates><Ribonucleotides><Role><Running><SARS corona virus 2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Scheme><Scientist><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Structural Protein><Structure><Sum><System><Technology><Testing><Time><Topoisomerase><Translating><Tumor Cell><Vitamin B 3><Vitamin B3><Vitamin PP><Work><Wuhan coronavirus><Zinc><Zn element><base><biological systems><bound protein><carcinogenicity><computational chemistry><computational resources><computing resources><conformation><conformational state><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 virus><cost><dGTP pyrophosphohydrolase><dGTP triphosphohydrolase><dGTPase><dRP lyase><deoxy-GTPase><deoxyguanosine triphosphatase><deoxyguanosine triphosphate triphosphohydrolase><drug resistant><drug/agent><functional hypothalamic amenorrhea><genome mutation><hCoV19><improved><interest><mechanical><mitochondrial><molecular dynamics><molecular mechanics><molecular modeling><multi-drug resistant><multidrug resistant><muscle structure><muscular structure><mutant><nCoV2><nano second><nanosecond><neoplastic cell><novel><peptide structure><protonation><quantum><resistance to Drug><resistant to Drug><simulation><small molecule><social role><tool>