| Full text | |
| Author(s): |
Total Authors: 3
|
| Affiliation: | [1] Univ Sao Paulo, Inst Quim, Dept Biochem, Sao Paulo - Brazil
[2] Oregon Hlth & Sci Univ, Sch Med, Dept Biomed Engn, Portland, OR 97201 - USA
Total Affiliations: 2
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| Document type: | Journal article |
| Source: | BIOPHYSICAL JOURNAL; v. 114, n. 5, p. 1058-1066, MAR 13 2018. |
| Web of Science Citations: | 12 |
| Abstract | |
The T4 lysozyme L99A mutant is often used as a model system to study small-molecule binding to proteins, but pathways for ligand entry and exit from the buried binding site and the associated protein conformational changes have not been fully resolved. Here, molecular dynamics simulations were employed to model benzene exit from its binding cavity using the weighted ensemble (WE) approach to enhance sampling of low-probability unbinding trajectories. Independent WE simulations revealed four pathways for benzene exit, which correspond to transient tunnels spontaneously formed in previous simulations of apo T4 lysozyme. Thus, benzene unbinding occurs through multiple pathways partially created by intrinsic protein structural fluctuations. Motions of several a-helices and side chains were involved in ligand escape from metastable microstates. WE simulations also provided preliminary estimates of rate constants for each exit pathway. These results complement previous works and provide a semiquantitative characterization of pathway heterogeneity for binding of small molecules to proteins. (AU) | |
| FAPESP's process: | 14/21900-2 - Development and application of computer simulation and spectroscopical analysis to study metalloenzymes and flexible proteins |
| Grantee: | Guilherme Menegon Arantes |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 16/24096-5 - Computer simulation of metalloenzymes and of flexible proteins |
| Grantee: | Guilherme Menegon Arantes |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 14/17008-7 - Computer simulation of rare biochemical phenomena by enhanced sampling methods |
| Grantee: | Ariane Ferreira Nunes Alves |
| Support Opportunities: | Scholarships in Brazil - Doctorate |
| FAPESP's process: | 15/19912-5 - Computer simulation of ligand exit pathways by the weighted ensemble method |
| Grantee: | Ariane Ferreira Nunes Alves |
| Support Opportunities: | Scholarships abroad - Research Internship - Doctorate |