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J Chem Inf Model. 2013 Mar 25;53(3):674-80. doi: 10.1021/ci300561b. Epub 2013 Feb 20.

Ligand binding site identification by higher dimension molecular dynamics.

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Department of Chemistry, Dartmouth College , Hanover, New Hampshire 03755, United States.


We propose a new molecular dynamics (MD) protocol to identify the binding site of a guest within a host. The method utilizes a four spatial (4D) dimension representation of the ligand allowing for rapid and efficient sampling within the receptor. We applied the method to two different model receptors characterized by diverse structural features of the binding site and different ligand binding affinities. The Abl kinase domain is comprised of a deep binding pocket and displays high affinity for the two chosen ligands examined here. The PDZ1 domain of PSD-95 has a shallow binding pocket that accommodates a peptide ligand involving far fewer interactions and a micromolar affinity. To ensure completely unbiased searching, the ligands were placed in the direct center of the protein receptors, away from the binding site, at the start of the 4D MD protocol. In both cases, the ligands were successfully docked into the binding site as identified in the published structures. The 4D MD protocol is able to overcome local energy barriers in locating the lowest energy binding pocket and will aid in the discovery of guest binding pockets in the absence of a priori knowledge of the site of interaction.

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