Finding multiple reaction pathways of ligand unbinding.
J Chem Phys
; 150(22): 221101, 2019 Jun 14.
Article
en En
| MEDLINE
| ID: mdl-31202231
ABSTRACT
Searching for reaction pathways describing rare events in large systems presents a long-standing challenge in chemistry and physics. Incorrectly computed reaction pathways result in the degeneracy of microscopic configurations and inability to sample hidden energy barriers. To this aim, we present a general enhanced sampling method to find multiple diverse reaction pathways of ligand unbinding through nonconvex optimization of a loss function describing ligand-protein interactions. The method successfully overcomes large energy barriers using an adaptive bias potential and constructs possible reaction pathways along transient tunnels without the initial guesses of intermediate or final states, requiring crystallographic information only. We examine the method on the T4 lysozyme L99A mutant which is often used as a model system to study ligand binding to proteins, provide a previously unknown reaction pathway, and show that by using the bias potential and the tunnel widths, it is possible to capture heterogeneity of the unbinding mechanisms between the found transient protein tunnels.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Benceno
/
Muramidasa
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
Idioma:
En
Revista:
J Chem Phys
Año:
2019
Tipo del documento:
Article
País de afiliación:
Polonia