The Application of Ligand-Mapping Molecular Dynamics Simulations to the Rational Design of Peptidic Modulators of Protein–Protein Interactions

Abstract

A computational ligand-mapping approach to detect protein surface pockets that interact with hydrophobic moieties is presented. In this method, we incorporated benzene molecules into explicit solvent molecular dynamics simulations of various protein targets. The benzene molecules successfully identified the binding locations of hydrophobic hot-spot residues and all-hydrocarbon cross-links from known peptidic ligands. They also unveiled cryptic binding sites that are occluded by side chains and the protein backbone. Our results demonstrate that ligand-mapping molecular dynamics simulations hold immense promise to guide the rational design of peptidic modulators of protein-protein interactions, including that of stapled peptides, which show promise as an exciting new class of cell-penetrating therapeutic molecules.

Stapled peptide design: principles and roles of computation

“…A special type of MD simulation method called ligand-mapping molecular dynamics (LMMD) has been shown to be effective at locating the shallow hydrophobic binding sites occupied by these hydrocarbon staples [82]. In LMMD, benzene molecules are used at low concentrations in explicit-solvent MD simulations of the target protein to probe for hydrophobic binding sites.…”

“…The positions sampled by the benzene probes during the simulations are then converted into occupancy maps that are represented by density grids. Such simulations have been successfully used to identify a novel ligand-binding mode at a cryptic binding pocket [83], enhance conformational sampling, and locate hydrophobic peptide binding sites [82,84]. The method was tested on five proteins that have known hydrocarbon staple interaction sites.…”

Gating by Tryptophan 73 Exposes a Cryptic Pocket at the Protein-Binding Interface of the Oncogenic eIF4E Protein

“…37−41 This approach along with others has been used successfully to reveal cryptic potentially druggable pockets in proteins. 37−41,57−61 Benzene was chosen as the hydrophobic solvent as it has recently been demonstrated to be a powerful probe 39,40 for the identification of novel potential ligand-binding sites on proteins. An exhaustive set of all-atom MD simulations of eIF4E starting from pure water to mixedsolvent comprised of water and benzene were conducted ( Table 2).…”

Targeting YAP/TAZ-TEAD protein-protein interactions using fragment-based and computational modeling approaches

“…[48,65] Briefly, TEAD (having excluded its binding partners present in the X-ray crystallography structures) was immersed in a box of water molecules with benzene molecules (around 0.2 M) placed randomly in solution (using the program packmol[66]). Ten independent 10 ns molecular dynamics simulations of the system were performed for each protein to allow the hydrophobic benzenes to open cryptic hydrophobic grooves and pockets not previously present in the crystal structure.…”