title: Both protein dynamics and ligand concentration can shift the binding mechanism between conformational selection and induced fit.
abstract: This study aimed to shed light on the long debate over whether conformational selection (CS) or induced fit (IF) is the governing mechanism for protein-ligand binding. The main difference between the two scenarios is whether the conformational transition of the protein from the unbound form to the bound form occurs before or after encountering the ligand. Here we introduce the IF fraction (i.e., the fraction of binding events achieved via IF), to quantify the binding mechanism. Using simulations of a model protein-ligand system, we demonstrate that both the rate of the conformational transition and the concentration of ligand molecules can affect the IF fraction. CS dominates at slow conformational transition and low ligand concentration. An increase in either quantity results in a higher IF fraction. Despite the many-body nature of the system and the involvement of multiple, disparate types of dynamics (i.e., ligand diffusion, protein conformational transition, and binding reaction), the overall binding kinetics over wide ranges of parameters can be fit to a single exponential, with the apparent rate constant exhibiting a linear dependence on ligand concentration. The present study may guide future kinetics experiments and dynamics simulations in determining the IF fraction.
authors: Department of Physics and Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306.
authors: Nicholas
authors: N
authors: Greives
authors: Department of Physics and Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306 hzhou4@fsu.edu.
authors: Huan-Xiang
authors: HX
authors: Zhou
mesh_terms: D007700:Kinetics; D008024:Ligands; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D011506:Proteins / Q000737:chemistry*
chemical_list: D008024:Ligands; D011506:Proteins
keywords: conformational dynamics; diffusion-influenced bimolecular reaction; induced-fit fraction; protein–ligand complex