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 deltaG 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.
Gostaria de agradecer ao meu orientador Sandro de Souza pelo apoio na minha vinda à São Paulo e pela oportunidade de trabalhar em seu laboratório. Ao meu co-orientador Richard Garratt pela paciência e pelas discussões sobre estruturas protéicas. Ao meu amigo Lars Juhl Jensen (EMBL) pela ajuda na manipulação dos resultados e análises estatísticas. Aos meus amigos do Laboratório de Biologia Computacional. Ao programa de pós-graduação em Bioinformática e seus funcionários. À CAPES pela bolsa de doutorado. Em especial, à minha família, especialmente meu marido e filho que estiveram tão perto de mim durante essa tese, me dando todo o carinho e apoio necessários.
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