Please use this identifier to cite or link to this item:
|Title:||Computational equilibrium thermodynamic and kinetic analysis of K-Ras dimerization through an effector binding surface suggests limited functional role|
Hancock, John F.
Gorfe, Alemayehu A.
|Citation:||Sayyed-Ahmad, A., Cho, K.J., Hancock, J.F. and Gorfe, A.A., 2016. Computational equilibrium thermodynamic and kinetic analysis of K-Ras dimerization through an effector binding surface suggests limited functional role. The Journal of Physical Chemistry B, 120(33), pp.8547-8556.|
|Abstract:||Dimer formation is believed to have a substantial impact on regulating K-Ras function. However, the evidence for dimerization and the molecular details of the process are scant. In this study, we characterize a K-Ras pseudo-C2-symmetric dimerization interface involving the effector interacting β2-strand. We used structure matching and all-atom molecular dynamics (MD) simulations to predict, refine, and investigate the stability of this interface. Our MD simulation suggested that the β2-dimer is potentially stable and remains relatively close to its initial conformation due to the presence of a number of hydrogen bonds, ionic salt bridges, and other favorable interactions. We carried out potential of mean force calculations to determine the relative binding strength of the interface. The results of these calculations indicated that the β2 dimerization interface provides a weak binding free energy in solution and a dissociation constant that is close to 1 mM. Analyses of Brownian dynamics simulations suggested an association rate kon ≈ 105–106 M–1 s–1. Combining these observations with available literature data, we propose that formation of auto-inhibited β2 K-Ras dimers is possible but its fraction in cells is likely very small under normal physiologic conditions.|
|Appears in Collections:||Fulltext Publications|
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.