TY  - UNPB
ID  - pittir11867
UR  - http://d-scholarship-dev.library.pitt.edu/11867/
A1  - Wang, David Wen Rui
Y1  - 2012/05/25/
N2  - Speeding the molecular binding process is of particular interest in many fields. While traditional belief dictates that ligand preorganization is optimal, the discovery of intrinsically disordered proteins may contest such convention. The ?fly-casting? mechanism argues that a flexible protein can bind its partner faster due to a larger capture radius and a resulting coupled process of folding and binding. We directly test this hypothesis, using computational means, on the p53-MDM2 system, performing binding simulations of MDM2 to either a flexible p53 peptide or its exact preorganized analog. We employ a path sampling algorithm, weighted ensemble, to generate large ensembles of binding pathways and to calculate rates of association. Additionally, the effect of hydrodynamic interactions, often omitted in implicit solvent simulations, on the binding rates was examined. We find no difference between the binding rates of flexible p53 and preorganized p53. The exclusion of hydrodynamic interactions significantly decreases the binding rates due to largely reduced translational diffusion coefficients, indicating the importance of using hydrodynamic interactions in binding simulations.
KW  - computer simulations
KW  -  p53-MDM2
KW  -  weighted ensemble
KW  -  flexibility vs preorganization
KW  -  hydrodynamic interactions
TI  - Flexibility vs. preorganization: molucular simulations of MDM2-p53 peptide binding events
EP  - 36
AV  - public
ER  -