Preference of Small Molecules for Local Minimum Conformations when Binding to Proteins

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.

Normal-Mode-Analysis–Monitored Energy Minimization Procedure for Generating Small–Molecule Bound Conformations

“…These observations are consistent with the report that approximately 70% of the small–molecule bound conformations in their protein-bound crystal structures have conformational strain energies of ≤3.0 kcal/mol [18]. These data are also consistent with our recently reported study of six small–molecule–protein complex crystal structures [9] in which 6 (100%), 5 (83%), 4 (67%), and 1 (17%) small–molecule bound conformations have the conformational strain energies of less than or equal to 2.3, 1.5, 0.88, and 0 kcal/mol, respectively. In this context, we propose to use a cut-off of 5.0 kcal/mol for the conformational strain energy to triage energetically less stable local minimum conformations in docking studies.…”

Enantioselective Binding of Propranolol and Analogues Thereof to Cellobiohydrolase Cel7A

“…For numerousm olecular recognition processes in nature, ligands bind to their receptors in one of its low-energys olution conformations. [16][17][18][19] This concept is referred to as conformational pre-organization andisenergetically favorable forab inding event as it lowers the entropy penalty upon association. [20] If the bioactive conformation of a ligandc orresponds to ah ighly populated conformation in solution,t his can thus representamajor drivingf orce for the interaction.…”

EUDOC on the IBM Blue Gene/L system: Accelerating the transfer of drug discoveries from laboratory to patient

“…However, the conformation induction approach is not ideal for docking studies because computing the mutually dependent conformational changes of both ligand and receptor is time consuming. Alternatively, the conformation selection theory involves a scenario in which both ligand and receptor select their preformed conformations that are most compatible with each other to effect binding by shifting two equilibriums progressively from less-compatible to most-compatible conformations for both partners [19][20][21][22][23][24], where the preformed conformations are conformations at the local minima of their potential energy surfaces (i.e., local minimum conformations). When the most compatible conformers of ligand and receptor are the most prevalent, the conformation selection theory becomes the lock-key theory [18].…”