Abstract
It is well known that small molecules (ligands) do not necessarily adopt their lowest potential energy conformations when binding to proteins. Analyses of protein-bound ligand crystal structures have reportedly shown that many of them do not even adopt the conformations at local minima of their potential energy surfaces (local minimum conformations). The results of these analyses raise a concern regarding the validity of virtual screening methods that use ligands in local minimum conformations. Here we report a normal-mode-analysis (NMA) study of 100 crystal structures of protein-bound ligands. Our data show that the energy minimization of a ligand alone does not automatically stop at a local minimum conformation if the minimum of the potential energy surface is shallow, thus leading to the folding of the ligand. Furthermore, our data show that all 100 ligand conformations in their protein-bound ligand crystal structures are nearly identical to their local minimum conformations obtained from NMA-monitored energy minimization, suggesting that ligands prefer to adopt local minimum conformations when binding to proteins. These results both support virtual screening methods that use ligands in local minimum conformations and caution about possible adverse effect of excessive energy minimization when generating a database of ligand conformations for virtual screening.
Highlights
Molecular complexation in biology is best described by the conformational induction theory [1]—namely, a ligand binds initially to a less compatible conformation of a receptor and adjusts its conformation to induce the most compatible conformation of the receptor
Before starting NMA, it was necessary to perform a few steps of energy minimization on a ligand conformation, taken from the ligand-protein complex crystal structure, in the absence of its protein partner to ‘‘adapt’’ the ligand to the force field used by the NMA as well as to reduce the gradient of the ligand potential energy to zero [15]
Within the context of the AMBER force field, these results indicate that all 100 ligand conformations in the crystal structures of their protein complexes are nearly identical to their local minimum conformations, demonstrating the preference of these ligands for local minimum conformations when binding to proteins
Summary
Molecular complexation in biology is best described by the conformational induction theory [1]—namely, a ligand (e.g., a small molecule) binds initially to a less compatible conformation of a receptor (e.g., a protein) and adjusts its conformation to induce the most compatible conformation of the receptor. The conformation induction theory is, not ideal for computationally addressing the conformational flexibility of both ligand and receptor in docking studies, because computing the mutually dependent conformational changes of both partners on the fly is time-consuming and unsuitable for parallel computing. The conformation selection theory is ideal to computationally account for molecular flexibility in docking, because it can convert a ligand–receptor association best described by the conformational induction theory to a series of associations each of which can be described by the lock-key theory [6]. The conformation selection theory thereby affords parallel computing and enables a docking study to be performed on thousands of IBM Blue Gene processors with high processor utilization [6,7,8]
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