A5077980797- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Enzyme Structure and Function
- Receptor Mechanisms and Signaling
- Pharmacogenetics and Drug Metabolism
- Eicosanoids and Hypertension Pharmacology
- Ion channel regulation and function
- Machine Learning in Materials Science
- RNA and protein synthesis mechanisms
- Nitric Oxide and Endothelin Effects
- Chemical Synthesis and Analysis
- Advanced Chemical Physics Studies
- Robot Manipulation and Learning
- Mass Spectrometry Techniques and Applications
- Fuel Cells and Related Materials
- Metal complexes synthesis and properties
- Muon and positron interactions and applications
- Analytical Chemistry and Chromatography
- Theoretical and Computational Physics
- Robotics and Automated Systems
- Innovative Microfluidic and Catalytic Techniques Innovation
- Advanced Thermodynamics and Statistical Mechanics
- Signaling Pathways in Disease
- Biotin and Related Studies
- Drug Transport and Resistance Mechanisms
Janssen (United States)
2022
Neurocrine Biosciences (United States)
2022
Cell Biologics (United States)
2022
Pfizer (United States)
2022
University of California, Irvine
2013-2020
University of Montana
2020
University of California, San Diego
2020
University of Maryland, College Park
2011
PVI System Technology (United States)
2009
Traditional approaches to specifying a molecular mechanics force field encode all the information needed assign parameters given molecule into discrete set of atom types. This is equivalent representation consisting graph comprising vertices, which represent atoms labeled by type, and unlabeled edges, chemical bonds. Bond stretch, angle bend, dihedral are then assigned looking up bonded pairs, triplets, quartets types in parameter tables valence terms using themselves nonbonded parameters....
Tremendous recent improvements in computer hardware, coupled with advances sampling techniques and force fields, are now allowing protein-ligand binding free energy calculations to be routinely used aid pharmaceutical drug discovery projects. However, despite these innovations, there still needs for further improvement algorithms more adequately sample protein motion relevant binding. Here, we report our work identifying studying such clear remaining the apolar cavity of T4 lysozyme L99A. In...
Accurately predicting protein–ligand binding affinities and modes is a major goal in computational chemistry, but even the prediction of ligand proteins poses challenges. Here, we focus on solving mode problem for rigid fragments. That is, computing dominant placement, conformation, orientations relatively rigid, fragment-like receptor, populations multiple which may be relevant. This important its own right, more timely given recent success alchemical free energy calculations. Alchemical...
Abstract Here, we focus on testing and improving force fields for molecular modeling, which see widespread use in diverse areas of computational chemistry biomolecular simulation. A key issue affecting the accuracy transferrability these is atom typing. Traditional approaches to defining mechanics must encode, within a discrete set types, all information will ever be needed about chemical environment; parameters are then assigned by looking up combinations types tables. This typing approach...
LEUNIG (LUG) and LEUNIG_HOMOLOG (LUH) encode two closely related Arabidopsis proteins, belonging to the Gro/TLE family of transcriptional co-repressors. These genes were previously shown exhibit partially overlapping functions in embryo flower development. In this report, role both LUH LUG on seed mucilage extrusion was examined. Seed occurs after seeds are imbibed, serving as functional aid hydration, germination, dispersal. While luh-1 mutants exhibited strong defects extrusion, lug-3 a...
A correct estimate of ligand binding modes and a ratio their occupancies is crucial for calculations free energies. The newly developed method BLUES combines molecular dynamics with nonequilibrium candidate Monte Carlo. Nonequilibrium Carlo generates plethora possible enables the system to relax. We used investigate caffeine in active site its metabolizing enzyme Cytochrome P450 1A2 aim elucidating metabolite-formation profiles at different concentrations. Because activation energies all...
Flexible ligands often have multiple binding modes or bound conformations that differ by rotation of a portion the molecule around internal rotatable bonds. Knowledge these is important for understanding interactions stabilizing ligand in pocket, and other studies indicate it calculating accurate affinities. In this work, we use hybrid molecular dynamics (MD)/nonequilibrium candidate Monte Carlo (NCMC) method to sample different several flexible also estimate population distribution modes....
Molecular simulations are a valuable tool for studying biomolecular motions and thermodynamics. However, such can be slow compared to simulation time scales, yet critical. Specifically, adequate sampling of side chain in protein binding pockets is crucial obtaining accurate estimates ligand free energies from molecular simulations. The scale rotamer flips range few ps several hundred ns or longer, particularly crowded environments like the interior proteins. Here, we apply mixed...
Inhibition of bacterial nitric oxide synthase (bNOS) has the potential to improve efficacy antimicrobials used treat infections by Gram-positive pathogens Staphylococcus aureus and Bacillus anthracis. However, inhibitor specificity toward bNOS over mammalian NOS (mNOS) isoforms remains a challenge because near identical active sites. One key structural difference between is amino acid composition pterin cofactor binding site that adjacent site. Previously, we demonstrated targeting both...
Production of nitric oxide (NO) by synthase (NOS) requires electrons to reduce the heme iron for substrate oxidation. Both FAD and FMN flavin groups mediate transfer NADPH derived NOS. Unlike mammalian NOS that contain both binding domains within a single polypeptide chain, bacterial is only composed an oxygenase domain must rely on separate redox partners electron subsequent activity. Here, we report native Bacillus subtilis (bsNOS) novel chimera promotes bsNOS By identifying characterizing...
Part of early stage drug discovery involves determining how molecules may bind to the target protein. Through understanding where and bind, chemists can begin build ideas on design improvements increase binding affinities. In this retrospective study, we compare computational approaches like docking, molecular dynamics (MD) simulations, a non-equilibrium candidate Monte Carlo (NCMC)-based method (NCMC + MD) perform in predicting modes for set 12 fragment-like molecules, which soluble epoxide...
Abstract Hv1 is a voltage-gated proton channel whose main function to facilitate extrusion of protons from the cell. The development effective blockers for can lead new therapeutics treatment maladies related dysfunction. Although mechanism permeation in remains be elucidated, series small molecules have been discovered inhibit Hv1. Here, we computed relative binding free energies prototypical blocker on model human an open state. We used alchemical energy perturbation techniques based...
Molecular simulations are a valuable tool for studying biomolecular motions and thermodynamics. However, such can be slow compared to simulation timescales, yet critical. Specifically, adequate sampling of sidechain in protein binding pockets proves crucial obtaining accurate estimates ligand free energies from molecular simulations. The timescale rotamer flips range few ps several hundred ns or longer, particularly crowded environments like the interior proteins. Here, we apply mixed...
Robotic control is a challenge for all applications, and simultaneous wireless of multiple robots an even greater challenge. In 2009, the FIRST Robotics Competition migrated to new system that relied on communication (802.11n standard) between controllers robots. This was developed implemented over course single year, nearly 2,000 teams competed with during 2009 season. The National Instruments (NI) CompactRIO embedded controller served as center system, this augmented additional hardware...
Part of early stage drug discovery involves determining how molecules may bind to the target protein. Through understanding where and bind, chemists can begin build ideas on design improvements increase binding affinities. In this retrospective study, we compare computational approaches like docking, molecular dynamics (MD) simulations, a non-equilibrium candidate Monte Carlo (NCMC) based method (NCMC+MD) perform in predicting modes for set 12 fragment-like which soluble epoxide hydrolase....
[4-(4-Methyl-2-(4-(trifluoromethyl)phenyl)thiazole-5-yl)pyrimidine-2-amine] (JNJ-2482272), under investigation as an anti-inflammatory agent, was orally administered to rats once daily at 60 mg/kg for 6 consecutive days. Despite high plasma exposure after single administration (Cmax of 7.1 μM), JNJ-2482272 had concentrations beneath the lower limit quantification (3 ng/ml) days dosing. To determine if is autoinducer in rats, plated rat hepatocytes were treated with 2 The major hydroxylated...
<div>Molecular simulations are a valuable tool for studying biomolecular motions and thermodynamics. However, such can be slow compared to simulation timescales, yet critical. Specifically, adequate sampling of sidechain in protein binding pockets proves crucial obtaining accurate estimates ligand free energies from molecular simulations. The timescale rotamer flips range few ps several hundred ns or longer, particularly crowded environments like the interior proteins. Here, we apply...
<div>Water molecules can be found interacting with the surface and within cavities in proteins. However, water exchange between bulk buried hydration sites slow compared to simulation timescales, thus leading inefficient sampling of locations water. This pose problems for free energy calculations computer-aided drug design. Here, we apply a hybrid method that combines nonequilibrium candidate Monte Carlo (NCMC) simulations molecular dynamics (MD) enhance specific areas system, such as...