Jiawen Chen and Zhong-Ru Xie contribute equally to this paper.
A multiscale model for simulating binding kinetics of proteins with flexible linkers
Article first published online: 9 JUN 2014
© 2014 Wiley Periodicals, Inc.
Proteins: Structure, Function, and Bioinformatics
Volume 82, Issue 10, pages 2512–2522, October 2014
How to Cite
Chen, J., Xie, Z.-R. and Wu, Y. (2014), A multiscale model for simulating binding kinetics of proteins with flexible linkers. Proteins, 82: 2512–2522. doi: 10.1002/prot.24614
- Issue published online: 24 SEP 2014
- Article first published online: 9 JUN 2014
- Accepted manuscript online: 30 MAY 2014 03:49AM EST
- Manuscript Accepted: 22 MAY 2014
- Manuscript Revised: 16 MAY 2014
- Manuscript Received: 31 MAR 2014
- Albert Einstein College of Medicine
- Monte-Carlo simulation;
- intrinsic disorder;
- cell signaling;
- conformational flexibility
The kinetics of protein interactions are essential determinants in many cellular processes such as signal transduction and transcriptional regulation. Many proteins involved in these functions contain intrinsic disordered regions. This makes conformational flexibility become an unneglectable factor when studying the binding kinetic of these proteins. Compared with the binding of rigid proteins that is limited by diffusions, the binding mechanisms of proteins with internal flexibility are much more complicated. Using a small protein that contains two domains and a connecting loop as a testing system, we developed a multiscale simulation framework to study the role of flexible linkers in regulating kinetics of protein binding. The association and dissociation processes were implemented by a coarse-grained Monte-Carlo algorithm, while the conformational changes of the flexible linker were captured from all-atom molecular dynamic simulations. Our simulations illustrated that the presence of the extended domain linker can enhance the rate of protein association. On the other hand, the full-length flexible molecule is more difficult to dissociate than its two rigid domains but much easier than the molecule with a rigid linker. Overall, our studies demonstrated that both kinetics and thermodynamics of protein binding are closely modulated by the dynamic features of linker regions. Proteins 2014; 82:2512–2522. © 2014 Wiley Periodicals, Inc.