Conformation Search Across Multiple-Level Potential-Energy Surfaces (CSAMP): A Strategy for Accurate Prediction of Protein–Ligand Binding Structures

Accurate
protein binding structure determination presents a great
challenge to both experiment and theory. Here, in this work, we propose
a new DOX protocol which combines the ensemble molecular Docking as
the coarse-level, structure Optimization with the semiempirical quantum
mechanics methods as the medium level, and the eXtended ONIOM (XO) calculations as the fine level. The fundamental of the
DOX protocol relies on the Conformation Search Across Multiple-level
Potential-energy surfaces (CSAMP) strategy, where the conformation
spaces of a funnel-like structure are searched from the coarse level
with hundreds of candidates to the medium level with around 10 top
candidates to the fine level with the final top 1 or 2 binding modes.
An in-depth test for the protocol set up against 28 crystallographic
data consisting of HMGR-statins, SDase-inhibitors, 3HNRase-inhibitors,
and NA-inhibitors yielded a satisfactory result with ∼0.5 Å
root-mean-square deviations (RMSDs) on geometries and ∼0.8
kcal/mol absolute error of relative binding energies on average. A
further larger scale validation on the Astex test set (including 85
diverse structures) revealed an impressive performance with a RMSD
< 2 Å success rate of 99%, suggesting DOX is a promising computational
route toward accurate prediction of the protein–ligand binding
structures.