Determine ligand binding kinetics to a membrane protein using Brownian dynamics simulation.

Abstract

Molecular diffusion controls the kinetics of protein-ligand binding in various biological processes. Determining the reaction rate between proteins and ligands is crucial in understanding these processes and in designing novel strategies to enhance or disrupt binding. Most previous studies focus on ligand diffusion in a three-dimensional bulk space. However, with the rapid growth of membrane protein research, a comprehensive understanding of molecular diffusion toward membrane-bound organelles or biomolecules tethered on a planar scaffold is essential. In this work, we developed a method that can predict the association rate constant of a ligand-membrane protein binding reaction according to trajectories from Brownian dynamics simulations. Our approach can be divided into two parts: 1) analytically determine the ligand association rate to a hemispherical region surrounding the membrane protein, and 2) compute the protein-ligand binding probability by Brownian dynamics simulations. We applied the method to calculate the reaction rate of biological systems with different charges. We found that the presence of a membrane does affect ligand diffusion, especially when the ligand moves close to the membrane. The critical aspects of surface diffusion, such as the forbidden zone, edge effect, and simulation criteria, were also discussed. Although the current development is based on a coarse-grained model, our method is still useful in understanding the binding kinetics of a highly complicated biological system.