Kinesin is a biological molecular motor that can move continuously on microtubule until it unbinds. Here, we studied computationally the force dependence of the unbinding rate of the motor. Our results showed that while the unbinding rate under the forward load has the expected characteristic of "slip bond", with the unbinding rate increasing monotonically with the increase of the forward load, the unbinding rate under the backward load shows counterintuitive characteristic of "slip-catch-slip bond": as the backward load increases, the unbinding rate increases exponentially firstly, then drops rapidly and then increases again. Our calculated data are in agreement with the available single-molecule data from different research groups. The mechanism of the slip-catch-slip bond was revealed.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bpc.2019.106216 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Estimation of Ligand Binding Free Energy Using Multi-eGO.
J Chem Inf Model
January 2025
Dipartimento di Bioscienze, Università degli Studi di Milano, Milan 20133, Italy.
The computational study of ligand binding to a target protein provides mechanistic insight into the molecular determinants of this process and can improve the success rate of drug design. All-atom molecular dynamics (MD) simulations can be used to evaluate the binding free energy, typically by thermodynamic integration, and to probe binding mechanisms, including the description of protein conformational dynamics. The advantages of MD come at a high computational cost, which limits its use.
View Article and Find Full Text PDFDilated cardiomyopathy variant R14del increases phospholamban pentamer stability, blunting dynamic regulation of calcium.
J Biol Chem
December 2024
Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL, USA. Electronic address:
The sarco(endo)plasmic reticulum Ca ATPase (SERCA) is a membrane transporter that creates and maintains intracellular Ca stores. In the heart, SERCA is regulated by an inhibitory interaction with the monomeric form of the transmembrane micropeptide phospholamban (PLB). PLB also forms avid homo-pentamers, and dynamic exchange of PLB between pentamers and SERCA is an important determinant of cardiac responsiveness to exercise.
View Article and Find Full Text PDFAnalysis of the Dynamics of a Complex, Multipathway Reaction: Insulin Dimer Dissociation.
J Phys Chem B
December 2024
Department of Chemistry, the University of Chicago, Chicago, Illinois 60637, United States.
The protein hormone insulin forms a homodimer that must dissociate to bind to its receptor. Understanding the kinetics and mechanism of dissociation is essential for the rational design of therapeutic analogs. In addition to its physiological importance, this dissociation process serves as a paradigm for coupled (un)folding and (un)binding.
View Article and Find Full Text PDFAdvances and Challenges in Milestoning Simulations for Drug-Target Kinetics.
J Chem Theory Comput
November 2024
Department of Molecular Biology, University of California San Diego, La Jolla, California 92093, United States.
Molecular dynamics simulations have become indispensable for exploring complex biological processes, yet their limitations in capturing rare events hinder our understanding of drug-target kinetics. In this Perspective, we investigate the domain of milestoning simulations to understand this challenge. The milestoning approach divides the phase space of the drug-target complex into discrete cells, offering extended time scale insights.
View Article and Find Full Text PDFProbing Single-Molecule Dynamics in Self-Assembling Viral Nucleocapsids.
Nano Lett
November 2024
Université Paris-Saclay, CNRS, Laboratoire de Physique des Solides, 91405 Orsay, France.
All viruses on Earth rely on host cell machinery for replication, a process that involves a complex self-assembly mechanism. Our aim here is to scrutinize in real time the growth of icosahedral viral nucleocapsids with single-molecule precision. Using total internal reflection fluorescence microscopy, we probed the binding and unbinding dynamics of fluorescently labeled capsid subunits on hundreds of immobilized viral RNA molecules simultaneously at each time point.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!