Biomaterial Database

Are induced fit protein conformational changes caused by ligand-binding predictable? A molecular dynamics investigation. 2017

Cen Gao, and Jeremy Desaphy, and Michal Vieth

Discovery chemistry, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Discovery Chemistry Research and Technologies, DC 1931, Indianapolis, Indiana, 46285.

In this work, the ability of molecular dynamics simulations (MD) to prospectively predict regions of ligand binding sites that could undergo induced fit effects was investigated. Conventional MD was run on 39 apo structures (no ligand), and the resulting trajectories were compared to a set of 147 holo X-ray structures (ligand-bound). It was observed from the simulations, in the absence of the ligands, that structures exhibiting large residue conformational changes indicated higher likelihood of induced fit effects. Nevertheless, the simulation results did not perform better than using the normalized crystallographic structural factors as predictors of active-site rigid residues (87% predictive power) and mobile residues (47% predictive power). While the simulations could not produce full active sites conformations similar to holo-like states, it was found that the simulations could reproduce bound state conformations of individual residues. These results suggest potential issues in the use of unligated simulation frames directly for drug design applications such as ligand docking, and an overall caution in the use of protein flexibility in docking protocols should be emphasized. © 2017 Wiley Periodicals, Inc.

UI	MeSH Term	Description	Entries
D008024	Ligands	A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed)	Ligand
D011485	Protein Binding	The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.	Plasma Protein Binding Capacity,Binding, Protein
D011487	Protein Conformation	The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain).	Conformation, Protein,Conformations, Protein,Protein Conformations
D011506	Proteins	Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.	Gene Products, Protein,Gene Proteins,Protein,Protein Gene Products,Proteins, Gene
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D001665	Binding Sites	The parts of a macromolecule that directly participate in its specific combination with another molecule.	Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining
D015195	Drug Design	The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis.	Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D017076	Computer-Aided Design	The use of computers for designing and/or manufacturing of anything, including drugs, surgical procedures, orthotics, and prosthetics.	CAD-CAM,Computer-Aided Manufacturing,Computer-Assisted Design,Computer-Assisted Manufacturing,Computer Aided Design,Computer Aided Manufacturing,Computer Assisted Design,Computer Assisted Manufacturing,Computer-Aided Designs,Computer-Assisted Designs,Design, Computer-Aided,Design, Computer-Assisted,Designs, Computer-Aided,Designs, Computer-Assisted,Manufacturing, Computer-Aided,Manufacturing, Computer-Assisted
D056004	Molecular Dynamics Simulation	A computer simulation developed to study the motion of molecules over a period of time.	Molecular Dynamics Simulations,Molecular Dynamics,Dynamic, Molecular,Dynamics Simulation, Molecular,Dynamics Simulations, Molecular,Dynamics, Molecular,Molecular Dynamic,Simulation, Molecular Dynamics,Simulations, Molecular Dynamics
D018360	Crystallography, X-Ray	The study of crystal structure using X-RAY DIFFRACTION techniques. (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed)	X-Ray Crystallography,Crystallography, X Ray,Crystallography, Xray,X Ray Crystallography,Xray Crystallography,Crystallographies, X Ray,X Ray Crystallographies