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Computer simulation of rare biochemical phenomena by enhanced sampling methods

Grant number: 14/17008-7
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): November 01, 2014
Effective date (End): October 31, 2017
Field of knowledge:Biological Sciences - Biochemistry - Chemistry of Macromolecules
Acordo de Cooperação: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Guilherme Menegon Arantes
Grantee:Ariane Ferreira Nunes Alves
Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated scholarship(s):15/19912-5 - Computer simulation of ligand exit pathways by the weighted ensemble method, BE.EP.DR


Rubredoxin is a protein commonly used as a model for studying the properties of iron-sulfur (Fe-s) metal centers. Recently, atomic force microscopy (AFM) experiments showed there is dependence of the rubredoxin forced unfolding kinetics and of the mechanical stability of its Fe-S bonds on the point of force application along the primary sequence. The reasons for such dependence, despite the tetrahedral symmetry of the Fe-S center, are unknown. Another protein commonly studied as a model for the binding of small ligands to macromolecules is the T4 lysozyme L99A mutant. Crystal structures suggest the artificial binding site created by the mutation has low accessibility, so a movement of "conformational breath" is necessary to allow the entrance of ligands. Although the cavity created by the mutation is well characterized, the conformational changes necessary to make it accessible to ligands are unknown. The forced unfolding of rubredoxin and the binding of small ligands to L99A are phenomena which occur in slow timescales and, therefore, they need methods of enhanced sampling to be studied appropriately by computational simulation. The aims of this project are to understand the dependence of the rubredoxin unfolding kinetics on the point of force application in AFM experiments and to determine the conformational mechanism which makes L99A artificial binding site accessible to small ligands. So, molecular dynamics simulations associated to steered molecular dynamics simulations, which allow enhanced sampling of unfolding events, and to umbrella sampling, which facilitates the overcoming of energetic barriers along a reaction path, will be employed. (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)
NUNES-ALVES, ARIANE; ARANTES, GUILHERME MENEGON. Mechanical Unfolding of Macromolecules Coupled to Bond Dissociation. JOURNAL OF CHEMICAL THEORY AND COMPUTATION, v. 14, n. 1, p. 282-290, . (14/21900-2, 16/24096-5, 14/17008-7)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
ALVES, Ariane Ferreira Nunes. Computer simulations of protein unfolding and ligand binding with enhanced sampling. 2017. Doctoral Thesis - Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ) São Paulo.

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