Structure and solvation of HIV-1-RT/inhibitors and furin/ha-substrate by molecular dynamics simulations

Abstract

The molecular dynamics (MD) simulations were applied in order to study changes of the structure, dynamic and solvation of protein via complexation with inhibitors and substrates, for the two systems: (i) HIV-1 reverse transcriptase (RT) complexed with the four non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz (EFV), emivirine (EMV), etravirine (ETV) and nevirapine (NVP) and (ii) Furin complexed with substrates, hemagglutinin subtypes H5 and H3 of the influenza A virus. In the first part, the MD simulations of the HIV-1 RT complexed with one of each of the four NNRTIs provide good evidence which deal with questions related to the mutation and free energy data. The binding free energy was found to decrease in the following order: EFV ~ ETV > EMV > NVP which is in good agreement with the experimentally derived IC50 values. On the basis of the calculation of the interaction energies, the L100, V106, Y181, Y188, F227, W229, P236, K101 and K103 amino acid residues show the largest contributions. Moreover, these residues are considered to be the most frequently detected mutated amino acids during treatment by various NNRTIs and, therefore, those most likely to find in the population for resistance. For the second part, origin of high pathogenicity of an emerging avian influenza H5N1 due to the –RRRKK– insertion at the cleavage loop of the hemagglutinin H5, was studied using the MD technique, in comparison with those of the non-inserted H5 and H3 bound to furin active site. The cleavage loop of the highly pathogenic H5 was found to bind strongly to the furin cavity, serving as a conformation suitable for the proteolytic reaction. Experimentally, the –RRRKK– insertion was also found to increase in cleavage of hemagglutinin by furin. The simulated data provide a clear answer to the question of why inserted H5 is better cleaved by furin than the other subtypes, explaining the high pathogenicity of avian influenza H5N1.