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Computer simulation of ligand exit pathways by the weighted ensemble method

Grant number: 15/19912-5
Support Opportunities:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): January 01, 2016
Effective date (End): June 29, 2016
Field of knowledge:Biological Sciences - Biochemistry - Chemistry of Macromolecules
Principal Investigator:Guilherme Menegon Arantes
Grantee:Ariane Ferreira Nunes Alves
Supervisor: Daniel Mark Zuckerman
Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Research place: University of Pittsburgh (Pitt), United States  
Associated to the scholarship:14/17008-7 - Computer simulation of rare biochemical phenomena by enhanced sampling methods, BP.DR


The T4 lysozyme L99A mutant is a protein often used to study small molecule binding to macromolecules. Crystal structures of the L99A mutant complexed with ligands show that the opening on the protein surface for ligand entry and scape from the engineered binding site is small. Thus, the protein must have a "conformational breath" to allow ligand excursion to the binding site. However, the conformational changes in T4 lysozyme L99A mutant necessary to allow ligand excursion to the engineered binding site are unknown. Binding events are hard to sample in a computer simulation because they involve transitions that are rare on the timescales usually reached in simulations. Thus, methods which reduce the waiting time for the occurrence of these rare transitions are necessary to allow sampling of binding events. The weighted ensemble (WE) approach is a computational method that enhances sampling of rare events in a simulation by increasing the sampling of low probability regions in a pre-defined reaction coordinate. WE allows the calculation of transition rates, which can be directly compared to experimental data, and is able to sample multiple pathways and reaction channels. Here, we propose to use the WE approach to sample pathways for ligand exit from the engineered binding site of T4 lysozyme L99A mutant and the necessary protein conformational changes that make the binding site accessible. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
NUNES-ALVES, ARIANE; ZUCKERMAN, DANIEL M.; ARANTES, GUILHERME MENEGON. Escape of a Small Molecule from Inside T4 Lysozyme by Multiple Pathways. BIOPHYSICAL JOURNAL, v. 114, n. 5, p. 1058-1066, . (14/21900-2, 16/24096-5, 14/17008-7, 15/19912-5)

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