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J Phys Chem B. 2009 Apr 9;113(14):4807-16. doi: 10.1021/jp803936q.

Exploring complex protein-ligand recognition mechanisms with coarse metadynamics.

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Computational Science, Department of Chemistry and Applied Biosciences, ETH Zurich, USI Campus, Via Giuseppe Buffi 13, CH-6900 Lugano, Switzerland.


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.

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