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Molecular dynamics simulations applied to the study of subtypes of HIV-1 protease common to Brazil, Africa, and Asia

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Abstract

Africa accounts for the majority of HIV-1 infections worldwide caused mainly by the A and C viral subtypes rather than B subtype, which prevails in the United States and Western Europe. In Brazil, B subtype is the major subtype, but F, C, and A also circulate. These non-B subtypes present polymorphisms, and some of them occur at sites that have been associated with drug resistance, including the HIV-1 protease (PR), one important drug target. Here, we report a Molecular Dynamics study of the B and non-B PR complexed with the inhibitor ritonavir to delineate the behavior of each subtype. We compare root mean squared deviation, binding free energy by linear interaction energy approach, hydrogen bonds, and intermolecular contact surface area between inhibitor and PR. From our results, we can provide a basis to understand the molecular mechanism of drug resistance in non-B subtypes. In this sense, we found a decrease of approx 4 kcal/mol in ΔG of binding between B and non-B subtypes. This corresponds to the loss of one hydrogen bond, which is in agreement with our H-bond analysis. Previous experimental affinity studies reported analogous results with inhibition constant values for non-B PR.

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Authors and Affiliations

  1. Laboratório de Modelagem e Dinâmica Molecular, Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

    Paulo R. Batista & Pedro G. Pascutti

  2. Laboratório Nacional de Computação Cientifica, Rio de Janeiro, Brazil

    Alan Wilter

  3. Instituoo Ludwig de Pesquisa sobre o Câncer, São Paulo, Brazil

    Elza H. A. B. Durham

  4. Instituto de Matemática e Estatistica, Universidade São Paulo, São Paulo, Brazil

    Paulo R. Batista, Alan Wilter, Elza H. A. B. Durham & Pedro G. Pascutti

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  1. Paulo R. Batista
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  3. Elza H. A. B. Durham
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  4. Pedro G. Pascutti
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Batista, P.R., Wilter, A., Durham, E.H.A.B. et al. Molecular dynamics simulations applied to the study of subtypes of HIV-1 protease common to Brazil, Africa, and Asia. Cell Biochem Biophys 44, 395–404 (2006). https://doi.org/10.1385/CBB:44:3:395

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