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

Ligand binding site identification by higher dimension molecular dynamics

Achani K Yatawara  1 , Milan Hodoscek, Dale F Mierke
Affiliations

Ligand binding site identification by higher dimension molecular dynamics

Achani K Yatawara et al. J Chem Inf Model. .

Abstract

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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Figures

Figure 1
Figure 1
Molecular structures and atomic nomenclature of the small molecule ligands bound to ABl-kinase, AGT and AMN-107.
Figure 2
Figure 2. The Abl-kinase/ATG complex
(A) the structure of the complex from the 4D MD protocol (protein green, ligand blue) superimposed with the ligand (orange) from the complex solved previously by X-ray. For reference the P-loop (residues 248–255) and activation loop (residues 381–402) are shown in red and magenta, respectively. (B) The interactions between ATG and Abl-kinase are shown schematically. The color coding of the protein amino acids indicate P-loop (red), activation loop (magenta), or other (green).
Figure 3
Figure 3. Variation of interatomic distances between atoms of ATG and the binding site during the simulation
The ligand reached the binding site around the 200th trajectory frame (towards the end of the 4D MD) and stayed inside the pocket throughout the simulation.
Figure 4
Figure 4. The Abl-kinase/AMN-107 complex
(A) the structure of the complex from the 4D MD protocol (protein green, ligand blue) superimposed with the ligand (orange) from the previous determined X-ray structure. For reference, the P-loop (residues 248–255) and activation loop (residues 381–402) are shown in red and magenta, respectively. (B) The interactions between AMN-107 and Abl-kinase are shown schematically. The color coding of the protein amino acids indicate P-loop (red), activation loop (magenta), or other (green).
Figure 5
Figure 5. The PDZ1 PSD-95/KQTSV complex
(A) the structure of the complex from the 4D MD protocol (protein green, ligand blue) superimposed with the ligand (orange) from the previous NMR structure., For reference the GLGF loop important for binding is shown in magenta. (B) The interactions between KQTSV and the PDZ1 domain are shown schematically. The interactions involving the GLGF loop are denoted by magenta and others in green.
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