Umbrella Sampling-Based Method to Compute Ligand-Binding Affinity

Son Tung Ngo; Minh Quan Pham

doi:10.1007/978-1-0716-1767-0_14

Umbrella Sampling-Based Method to Compute Ligand-Binding Affinity

Methods Mol Biol. 2022:2385:313-323. doi: 10.1007/978-1-0716-1767-0_14.

Authors

Son Tung Ngo^{1

2}, Minh Quan Pham^{3

4}

Affiliations

¹ Laboratory of Theoretical and Computational Biophysics, Ton Duc Thang University, Ho Chi Minh City, Vietnam. ngosontung@tdtu.edu.vn.
² Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam. ngosontung@tdtu.edu.vn.
³ Graduate University of Science and Technology, Vietnam Academy of Science and Technology, Hanoi, Vietnam.
⁴ Institute of Natural Products Chemistry, Vietnam Academy of Science and Technology, Hanoi, Vietnam.

PMID: 34888726
DOI: 10.1007/978-1-0716-1767-0_14

Abstract

Many proteins have a solvent-exposed binding cleft, which permits their inhibitors to bind and unbind without significant protein conformation transforms. The binding/unbinding pathways of these protein-inhibitor complexes can be rather straightforwardly sampled by using umbrella sampling (US) simulation methods. During a US simulation, the C_α atoms of the protein are restrained via a harmonic force. The potential of mean force (PMF) along the binding pathway can be estimated by using the weighted histogram analysis method (WHAM). The binding affinity is then computed as the difference in PMF between the binding and unbinding states.

Keywords: Biased sampling; Ligand-binding free energy; Potential of mean force; Steered MD; Umbrella sampling; WHAM calculation.

MeSH terms

Ligands
Molecular Dynamics Simulation
Protein Binding
Protein Conformation
Proteins / metabolism*
Solvents
Thermodynamics

Substances

Ligands
Proteins
Solvents