Multiple Ligand Unbinding Pathways and Ligand-Induced Destabilization Revealed by WExplore.
Biophys J
; 112(4): 620-629, 2017 Feb 28.
Article
em En
| MEDLINE
| ID: mdl-28256222
ABSTRACT
We report simulations of full ligand exit pathways for the trypsin-benzamidine system, generated using the sampling technique WExplore. WExplore is able to observe millisecond-scale unbinding events using many nanosecond-scale trajectories that are run without introducing biasing forces. The algorithm generates rare events by dividing the coordinate space into regions, on-the-fly, and balancing computational effort between regions through cloning and merging steps, as in the weighted ensemble method. The averaged exit flux yields a ligand exit rate of 180 µs, which is within an order of magnitude of the experimental value. We obtain broad sampling of ligand exit pathways, and visualize our findings using conformation space networks. The analysis shows three distinct exit channels, two of which are formed through large, rare motions of the loop regions in trypsin. This broad set of ligand-bound poses is then used to investigate general properties of ligand binding we observe both a direct stabilizing effect of ligand-protein interactions and an indirect destabilizing effect on intraprotein interactions that is induced by the ligand. Significantly, the crystallographic binding poses are distinguished not only because their ligands induce large stabilizing effects, but also because they induce relatively low indirect destabilizations.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Benzamidinas
/
Tripsina
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article