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Luis Paulo. B. Scott

Luis Paulo. B. Scott

Universidade Federal do ABC , Brazil

Title: A new protocol to investigate conformational population patterns in the enzymatic activity cycle of proteins using molecular dynamics and normal mode analysis

Biography

Biography: Luis Paulo. B. Scott

Abstract

Human immunodeficiency virus type-1 protease (HIV-1 PR) is an aspartic protease whose proteolytic activity is essential for cleaving precursor viral polyproteins into individual proteins implied in viral replication. Once HIV enters within a host cell, its RNA is transcribed into DNA through reverse transcriptase, integrated and amplified along with the replication of the host cell's DNA. Gag and gag-pro-pol genes are transcribed into messenger RNA, translated into gag and gag-pro-pol precursors proteins in the cytoplasm, and then assembled at the cell surface for budding and formation of the immature viral particles. In this work, we propose a computational protocol to generate and select HIV protease conformations relevant to its function using Normal Mode Analysis (NMA). We have considered structures of the apoenzyme, the protein with its substrate and product and the protein with a drug.  This set of structures should reveal large amplitude motions that are critical to the protease activity cycle as: i) substrate acquisition; ii) substrate cleavage and; iii) product release. The apoenzyme presents an increased flap conformational diversity compared to the various complexes, predominantly populated with open flap conformations, that can possibly be related to the substrates acquisition.  The enzyme-substrate complexes show more structural diversity than enzyme-product complexes, suggesting a role of these conformational changes in catalytic activity. We presents a promising protocol to identify the conformational diversity induced by different types of ligands and that can help the drug design process.

 

References:

  1. Lima, A N. ; Philot, E. A. ; TROSSINI, G. ; SCOTT, L. P. B. ; MALTAROLLO, V. ; HONORIO, K. M. . Use of machine learning approaches for novel drug discovery. Expert Opinion on Drug Discovery (Print), v. 11, p. 225-239, 2016.
  2. MEISSNER, G. ; RESENDE-LARA, P. ; MATSUBARA, F. ; Luis P B Scott ; BRAZ, ANTÔNIO S.K. ; CHAVES-MOREIRA, D. ; SOARES, E. ; TREVISAN-SILVA, D. ; GREMSKI, L. ; VEIGA ; CHAIM, O. . Molecular cloning and in silico characterization of knottin peptide, U2-SCRTX-Lit2, from brown spider (Loxosceles intermedia) venom glands. Journal of Molecular Modeling (Online), v. 22, p. 196, 2016.
  3. ARAUJO, G. ; Silva, R H T ; SCOTT, L. P. B. ; ARAUJO, A. S. ; SOUZA, F. P. ; OLIVEIRA, R. J. . Structure and functional dynamics characterization of the ion channel of the human respiratory syncytial virus (hRSV) small hydrophobic protein (SH) transmembrane domain by combining molecular dynamics with excited normal modes. Journal of Molecular Modeling (Print) , v. 22, p. 3-8, 2016.
  4. Philot, E. A. ; LOPES, D. M. ; SOUZA, A. T. ; BRAZ, A. S. K. ; NANTES, I. L. ; RODRIGUES, T. ; Perahia, D. ; MITEVA, M. A. ; SCOTT, L. P. B. . Binding of phenothiazines into allosteric hydrophobic pocket of human thioredoxin 1. European Biophysics Journal, v. 43, p. 2798-286, 2016.
  5. CONTO, V. ; BRAZ, A. S. K. ; Perahia, D. ; SCOTT, L. P. B. . Recovery of the wild type atomic flexibility in the HIV-1 protease double mutants. Journal of Molecular Graphics & Modelling , v. 59c, p. 107-116, 2015.