Abstract
Ligand–protein association is the first and critical step for many biological and chemical processes. This study investigated the molecular association processes under different environments. In biology, cells have different compartments where ligand–protein binding may occur on a membrane. In experiments involving ligand–protein binding, such as the surface plasmon resonance and continuous flow biosynthesis, a substrate flow and surface are required in experimental settings. As compared with a simple binding condition, which includes only the ligand, protein, and solvent, the association rate and processes may be affected by additional ligand transporting forces and other intermolecular interactions between the ligand and environmental objects. We evaluated these environmental factors by using a ligand xk263 binding to HIV protease (HIVp) with atomistic details. Using Brownian dynamics simulations, we modeled xk263 and HIVp association time and probability when a system has xk263 diffusion flux and a non-polar self-assembled monolayer surface. We also examined different protein orientations and accessible surfaces for xk263. To allow xk263 to access to the dimer interface of immobilized HIVp, we simulated the system by placing the protein 20Å above the surface because immobilizing HIVp on a surface prevented xk263 from contacting with the interface. The non-specific interactions increased the binding probability while the association time remained unchanged. When the xk263 diffusion flux increased, the effective xk263 concentration around HIVp, xk263–HIVp association time and binding probability decreased non-linearly regardless of interacting with the self-assembled monolayer surface or not. The work sheds light on the effects of the solvent flow and surface environment on ligand–protein associations and provides a perspective on experimental design.
Highlights
Molecular association is the first critical step in all chemical and biological processes such as the immune response, signal transduction, drug-protein binding, and chemical catalysis (Ozbabacan et al, 2010; Dill and Bromberg, 2012; Baron and McCammon, 2013; Lin et al, 2020)
Because this study focuses on the initial molecular encounter processes, we chose a flap open conformation and used rigid-body Brownian dynamics (BD) simulations to model the ligand association
In experimental settings such as using Surface plasmon resonance (SPR) to study ligand–protein binding, the choice of the surface and the flow rate are all optimized for measurements
Summary
Molecular association is the first critical step in all chemical and biological processes such as the immune response, signal transduction, drug-protein binding, and chemical catalysis (Ozbabacan et al, 2010; Dill and Bromberg, 2012; Baron and McCammon, 2013; Lin et al, 2020). Diffusion-controlled association rate constants may Ligand-Protein Association in Diverse Conditions be approximated analytically, most ligand–protein systems have slower association rates than the diffusion-limited rate because the association event involves multiple steps (Di Cera, 2017; Pang and Zhou, 2017). Conformational rearrangement of both molecules largely determines their binding kinetics, but the two molecules must have an initial encounter first. This first step may be greatly affected by the environment, which can result in different measured association-rate constants. The choice of surface and flow rate usually need to be optimized for various systems
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