Large-scale conformational changes of Trypanosoma cruzi proline racemase predicted by accelerated molecular dynamics simulation.
Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is a life-threatening illness affecting 11-18 million people. Currently available treatments are limited, with unacceptable efficacy and safety profiles. Recent studies have revealed an essential T. cruzi proline racemase enzyme (TcPR) as an attractive candidate for improved chemotherapeutic intervention. Conformational changes associated with substrate binding to TcPR are believed to expose critical residues that elicit a host mitogenic B-cell response, a process contributing to parasite persistence and immune system evasion. Characterization of the conformational states of TcPR requires access to long-time-scale motions that are currently inaccessible by standard molecular dynamics simulations. Here we describe advanced accelerated molecular dynamics that extend the effective simulation time and capture large-scale motions of functional relevance. Conservation and fragment mapping analyses identified potential conformational epitopes located in the vicinity of newly identified transient binding pockets. The newly identified open TcPR conformations revealed by this study along with knowledge of the closed to open interconversion mechanism advances our understanding of TcPR function. The results and the strategy adopted in this work constitute an important step toward the rationalization of the molecular basis behind the mitogenic B-cell response of TcPR and provide new insights for future structure-based drug discovery.
Departments of Chemistry and Biochemistry, Howard Hughes Medical Institute, Center for Theoretical Biological Physics, University of California, San Diego, La Jolla, California, United States of America. cesar@mccammon.ucsd.edu
César Augusto F
CA
de Oliveira
Barry J
BJ
Grant
Michelle
M
Zhou
J Andrew
JA
McCammon
D000591:Amino Acid Isomerases / Q000737:chemistry*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D025341:Principal Component Analysis; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000737:chemistry*; D014349:Trypanosoma cruzi / Q000201:enzymology* / Q000276:immunology
D015800:Protozoan Proteins; D000591:Amino Acid Isomerases; C022451:proline racemase