Exploring complex protein-ligand recognition mechanisms with coarse metadynamics.
The metadynamics method has been shown to be a valuable tool to study the mechanism of molecular recognition in atomistic detail [Gervasio, F. L.; et al. J. Am. Chem. Soc. 2005, 127, 2600]. However, it requires an a priori knowledge of all slow degrees of freedom relevant to the docking/undocking mechanism. Here we investigate a combination of docking/clustering with metadynamics performed with a subset of the necessary degrees of freedom (coarse metadynamics), and show that it provides a full mechanistic insight on the protein-ligand docking mechanism. Moreover, the proposed protocol is able to clearly distinguish between crystallographic and noncrystallographic poses of protein-ligand complexes, and also to find the transition state of the full undocking mechanism, thus giving an indication on the binding free energy.
Masetti
Matteo
M
Computational Science, Department of Chemistry and Applied Biosciences, ETH Zurich, USI Campus, Via Giuseppe Buffi 13, CH-6900 Lugano, Switzerland.
Cavalli
Andrea
A
Recanatini
Maurizio
M
Gervasio
Francesco Luigi
FL
D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors / Q000737:chemistry*; D004926:Escherichia coli / Q000201:enzymology; D047628:Estrogen Receptor alpha / Q000737:chemistry* / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000071679:Glycogen Synthase Kinase 3 beta; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013816:Thermodynamics; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology; D014260:Triclosan / Q000737:chemistry* / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D047628:Estrogen Receptor alpha; D008024:Ligands; D013844:Thiazoles; D013629:Tamoxifen; C016601:afimoxifene; D014260:Triclosan; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3