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J Biomol Struct Dyn. 2019 Jun 11:1-10. doi: 10.1080/07391102.2019.1626769. [Epub ahead of print]

Studying effects of different protonation states of His11 and His102 in ribose-5-phosphate isomerase of Trypanosoma cruzi: an example of cooperative behavior.

Author information

1
a Grupo de Biofísica Computacional e Modelagem Molecular , Programa de Computação Científica , Fiocruz , Rio de Janeiro , Brasil.
2
b Laboratório de Modelagem Molecular e Planejamento de Fármacos, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas , Universidade Federal de Minas Gerais , Belo Horizonte , Brasil.
3
c Laboratório de Genômica Funcional e Bioinformática , Instituto Oswaldo Cruz , Fiocruz , Rio de Janeiro , Brasil.

Abstract

The Trypanosoma cruzi ribose-5-phosphate isomerase B (TcRpiB) is a crucial piece in the pentose phosphate pathway and thus is a potential drug target for treatment of Chagas' disease. TcRpiB residues, such as Cys69, Asp45, Glu149 and Pro47, have confirmed their roles in substrate recognition, catalytic reaction and binding site conformation. However, the joint performance of His11 and His102, in the D-ribose-5-phosphate (R5P) in the catalysis is not well understood. In this work, we probed the influence of different protonation states of His11 and His102 on the behavior of the ligand R5P using molecular dynamics simulations, network analysis and thermodynamic integration. Simulations revealed that a protonated His11 combined with a neutral His102 (His11+‒His102) was able to stabilize the ligand R5P in the binding site. Moreover, calculated relative free energy differences showed that when protonated His11 was coupled to a neutral His102 an exergonic process takes place. On the other hand, neutral His11 combined with a protonated His102 (His11‒His102+), sampled conformations that resembled the catalyzed product D-ribulose-5-phosphate (Ru5P). Network analysis also demonstrated some peculiarities for these systems with some negatively correlated nodes in the binding site for His11‒His102+, and exclusive suboptimal paths for His11+‒His102. Therefore, the combined approach presented in this paper proposes two suitable protonation states for the TcRpiB catalytic mechanism, where an extra proton in either histidines might favor R5P binding or influence isomerization reaction to Ru5P. Our results may guide further in silico drug discovery studies. Abbreviations HsRpiA ribose-5-phsphate isomerase A from Homo sapiens LmRpiB ribose-5-phsphate isomerase B from Leishmania major MD molecular dynamics PDB protein data bank PME particle mesh Ewald R5P D-ribose-5-Phosphate Ru5P D-ribulose-5-phosphate RMSD Root mean square deviation RMSF root mean square fluctuation TcRpiB ribose-5-phsphate isomerase B from Trypanosoma cruzi Communicated by Ramaswamy H. Sarma.

KEYWORDS:

Trypanosoma cruzi; molecular dynamics simulation; network models; ribose-5-phosphate isomerase; thermodynamic integration

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