Bridging Molecular Docking to Molecular Dynamics in Exploring Ligand-Protein Recognition Process: An Overview

Abstract

Computational techniques have been applied in the drug discovery pipeline since the 1980s. Given the low computational resources of the time, the first molecular modeling strategies relied on a rigid view of the ligand-target binding process. During the years, the evolution of hardware technologies has gradually allowed simulating the dynamic nature of the binding event. In this work, we present an overview of the evolution of structure-based drug discovery techniques in the study of ligand-target recognition phenomenon, going from the static molecular docking toward enhanced molecular dynamics strategies.

Keywords: enhanced sampling; ligand-protein binding; molecular docking; molecular dynamics; molecular recognition; protein flexibility.

Figure 1

Molecular docking techniques organized according to ligand-protein flexibility and conformational searching engines.

Figure 2

Schematic representation of a molecular dynamics cycle.

Figure 3

Summary of the enhanced sampling techniques described during this work.

Figure 4

(A) Sketch of a pepSuMD step: the distance between the centers of mass of the ligand (peptide) and the target is computed at regular time intervals during the SuMD step. The distance values are fitted by a line, whose slope (m) determines if the current SuMD step (m > 0) or a new one (m < 0) has to be simulated. (B) Representation of the binding pathway bringing BAD peptide to the Bcl-X_L binding site, occurring in 46.2 ns. The superposition of the final pepSuMD state with the experimental structure (PDB ID: 1G5J, Petros et al., 2000) is reported on the right.