A5051959591- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Spectroscopy and Quantum Chemical Studies
- Enzyme Structure and Function
- Advanced Thermodynamics and Statistical Mechanics
- Phase Equilibria and Thermodynamics
- thermodynamics and calorimetric analyses
- Drug Solubulity and Delivery Systems
- Machine Learning in Materials Science
- Rheology and Fluid Dynamics Studies
- Microfluidic and Capillary Electrophoresis Applications
- Innovations in Concrete and Construction Materials
- Chemical Synthesis and Analysis
- Receptor Mechanisms and Signaling
- Process Optimization and Integration
- Chemical and Physical Properties in Aqueous Solutions
- Fuel Cells and Related Materials
- Protein Interaction Studies and Fluorescence Analysis
- Click Chemistry and Applications
- Genetics, Bioinformatics, and Biomedical Research
- Neurotransmitter Receptor Influence on Behavior
- Cancer therapeutics and mechanisms
- Free Radicals and Antioxidants
- HER2/EGFR in Cancer Research
- Thermal and Kinetic Analysis
The Graduate Center, CUNY
2016-2025
City University of New York
2016-2025
Lehman College
2016-2025
Rutgers, The State University of New Jersey
2019
AmberTools is a free and open-source collection of programs used to set up, run, analyze molecular simulations. The newer features contained within AmberTools23 are briefly described in this Application note.
Recently much effort has been invested in using convolutional neural network (CNN) models trained on 3D structural images of protein-ligand complexes to distinguish binding from non-binding ligands for virtual screening. However, the dearth reliable x-ray structures and affinity data required use constructed datasets training evaluation CNN molecular recognition models. Here, we outline various sources bias one such widely-used dataset, Directory Useful Decoys: Enhanced (DUD-E). We have...
Water molecules in the active site of an enzyme occupy a complex, heterogeneous environment, and thermodynamic properties active-site water are functions position. As consequence, it is thought that inhibitor can gain affinity by extending into region occupied unfavorable or lose displacing from where was relatively stable. Recent advances characterization binding-site water, based on analysis molecular simulations with explicit molecules, have focused largely simplified representations as...
The expulsion of water from surfaces upon molecular recognition and nonspecific association makes a major contribution to the free energy changes these processes. In order facilitate characterization structure thermodynamics on surfaces, we have incorporated Grid Inhomogeneous Solvation Theory (GIST) into CPPTRAJ toolset AmberTools. GIST is grid‐based implementation Fluid Theory, which analyzes output dynamics simulations map out solvation thermodynamic structural properties high‐resolution,...
Significance Water molecules play a crucial role in protein–ligand binding. Calculating the energetic consequences of displacing water upon ligand binding has challenged field for many years. Inhomogeneous solvation theory (IST) is one most popular methods distinguishing favorable from unfavorable molecules, but little controlled, prospective testing at atomic resolution been done to evaluate method. Here we compare molecular docking screens with and without an IST term gauge its impact on...
<p>Recently much effort has been invested in using convolutional neural network (CNN) models trained on 3D structural images of protein-ligand complexes to distinguish binding from non-binding ligands for virtual screening. However, the dearth reliable x-ray structures and affinity data required use constructed datasets training evaluation CNN molecular recognition models. Here, we outline various sources bias one such widely-used dataset, Directory Useful Decoys: Enhanced (DUD-E). We...
We have developed SSTMap, a software package for mapping structural and thermodynamic water properties in molecular dynamics trajectories. The introduces automated analysis of local measures frustration enhancement structure. calculations are based on Inhomogeneous Fluid Solvation Theory (IST), which is implemented using both site-based grid-based approaches. also extends the applicability solvation to multiple (MD) simulation programs by existing cross-platform tools parsing MD parameter...
Traditional molecular dynamics (MD) simulations of proteins, which relies on integration Newton's equations motion, cannot efficiently equilibrate water occupancy for buried cavities in proteins. This leads to slow convergence thermodynamic averages such systems. We have addressed this challenge by integrating standard Metropolis Monte Carlo (MC) translational moves with MD the AMBER simulation package. The allow easily enter or exit sites a thermodynamically correct way during simulation....
A number of computational tools available today compute the thermodynamic properties water at surfaces and in binding pockets by using inhomogeneous solvation theory (IST) to analyze explicit-solvent simulations. Such methods enable qualitative spatial mappings both energy entropy around a solute interest can also be applied quantitatively. However, estimates existing have, date, been almost entirely limited first-order terms IST's expansion. These account for localization orientation...
The principles underlying water reorganization around simple nonpolar solutes are well understood and provide the framework for classical hydrophobic effect, whereby molecules structure themselves so that they maintain favorable energetic contacts with both solute other molecules. However, certain surface topographies, molecules, due to their geometry size, unable simultaneously neighboring In this study, we analyze solvation of ligand-binding sites six structurally diverse proteins using...
Molecular docking methods are widely used in drug discovery efforts. RAS proteins important cancer targets, and useful systems for evaluating methods, including accounting solvation effects covalent small molecule binding. Water often plays a key role binding to proteins, many inhibitors─including FDA-approved drugs─covalently bind oncogenic proteins. We assembled test set, consisting of 138 protein structures 2 KRAS DNA complex with ligands. In DOCK 6, we have implemented receptor...
Conformational flexibility complicates the identification of lead molecules that are shape and charge complementary to target proteins. Solvation thermodynamics has typically not been integrated into exploration alternate protein conformations. Here, we study variation solvation thermodynamic potentials as proteins adopt different Specifically, analyze binding cavities with conformations obtained from molecular dynamics simulations mobile side chains restrained about their cognate bound...
A statistical-mechanical framework for estimation of solvation entropies and enthalpies is proposed, which based on the analysis water as a mixture correlated oxygens hydrogens. Entropic contributions increasing order are cast in terms Mutual Information Expansion that evaluated to pairwise interactions. In turn, enthalpy computed directly from distance-based hydrogen bonding energy algorithm. The resulting expressions employed grid-based analyses Molecular Dynamics simulations. this first...
Force field accuracy is still one of the “stalemates” in biomolecular modeling. Model systems with high quality experimental data are valuable instruments for validation and improvement effective potentials. With respect to protein–ligand binding, organic host–guest complexes have long served as models both computational studies because abundance binding affinity available such systems. Binding collected cyclodextrin (CD) inclusion complexes, a popular model molecular recognition,...
Computed, high-resolution, spatial distributions of solvation energy and entropy can provide detailed information about the role water in molecular recognition. While grid inhomogeneous theory (GIST) provides rigorous, thermodynamic from explicit solvent dynamics simulations, recent developments 3D reference interaction site model (3D-RISM) allow many same quantities to be calculated a fraction time. However, 3D-RISM produces atomic-site, rather than molecular, density distributions, which...
Grid Inhomogeneous Solvation Theory (GIST) maps out solvation thermodynamic properties on a fine meshed grid and provides statistical mechanical formalism for end-state calculations. However, differences in how long-range nonbonded interactions are calculated molecular dynamics engines the current implementation of GIST have prevented precise comparisons between free energies estimated using those from other energy methods such as integration (TI). Here, we address this by presenting...
Abstract In this study, we demonstrate a method to construct water-based pharmacophore model which can be utilized in the absence of known ligands. This utilizes waters found binding pocket, sampled through molecular dynamics. Screening compound databases against reveals that approach successfully identify binders target protein. The was tested by enrichment studies 7 therapeutically important targets and compared favourably screening-by-docking with Glide. Our results suggest even without...
The concept that a fluid has position-dependent free energy density appears in the literature but not been fully developed or accepted. We set this on an unambiguous theoretical footing via following strategy. First, we forth four desiderata should be satisfied by any definition of density, f(R), system comprising only and rigid solute: its volume integral, plus fixed internal solute, energy; it deviates from bulk value, fbulk, near solute asymptotically approach fbulk with increasing...
The concept that a fluid has position-dependent free energy density appears in the literature but not been fully developed or accepted. We set this on an unambiguous theoretical footing via following strategy. First, we forth four desiderata should be satisfied by any definition of density, f(R), system comprising only and rigid solute: its volume integral, plus fixed internal solute, energy; it deviates from bulk value, f_bulk, near solute asymptotically approach f_bulk with increasing...
This study investigates the role of hydration and its relationship to conformational equilibrium host molecule β-cyclodextrin. Molecular dynamics simulations indicate that unbound β-cyclodextrin exhibits two state behavior in explicit solvent due opening closing cavity. In implicit solvent, these transitions are not observed, there is one dominant conformation with an open Based on observations, we investigate hypothesis expulsion thermodynamically unfavorable water molecules into bulk plays...
A series of analogues featuring a 6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol unit as the arylamine "head" group classical D3 antagonist core structure were synthesized and evaluated for affinity at dopamine D1, D2, receptors (D1R, D2R, D3R). The compounds generally displayed strong D3R with very good selectivity. Docking studies D2R crystal structures revealed that molecules are oriented such their units positioned in orthosteric binding pocket D3R, arylamide "tail" residing secondary...
Confined hydration and conformational flexibility are some of the challenges encountered for rational design selective antagonists G-protein coupled receptors. We present a set C3-substituted (-)-stepholidine derivatives as potent binders dopamine D3 receptor. The compounds characterized biochemically, well by computer modeling using novel molecular dynamics-based alchemical binding free energy approach which incorporates effect displacement enclosed water molecules from site. specific sites...