Relation between flexibility and positively selected HIV‐1 protease mutants against inhibitors

Abstract

The antiretroviral chemotherapy helps to reduce the mortality of HIVs infected patients. However, RNA dependant virus replication has a high mutation rate. Human immunodeficiency virus Type 1 protease plays an essential role in viral replication cycle. This protein is an important target for therapy with viral protein inhibitors. There are few works using normal mode analysis to investigate this problem from the structural changes viewpoint. The investigation of protein flexibility may be important for the study of processes associated with conformational changes and state transitions. The normal mode analysis allowed us to investigate structural changes in the protease (such as flexibility) in a straightforward way and try to associate these changes with the increase of fitness for each positively selected HIV-1 mutant protease of patients treated with several protease inhibitors (saquinavir, indinavir, ritonavir, nelfinavir, lopinavir, fosamprenavir, atazanavir, darunavir, and tripanavir) in combination or separately. These positively selected mutations introduce significant flexibility in important regions such as the active site cavity and flaps. These mutations were also able to cause changes in accessible solvent area. This study showed that the majority of HIV-1 protease mutants can be grouped into two main classes of protein flexibility behavior. We presented a new approach to study structural changes caused by positively selected mutations in a pathogen protein, for instance the HIV-1 protease and their relationship with their resistance mechanism against known inhibitors. The method can be applied to any pharmaceutically relevant pathogen proteins and could be very useful to understand the effects of positively selected mutations in the context of structural changes.

A Cluster Analysis on the Structural Diversity of Protein Crystals, Exemplified by Human Immunodeficiency Virus Type 1 Protease

“…The cantilever region from codons 59 to 75 composes a long antiparallel β-sheet and has a mechanical role for opening and closing of the flap region as well as for stabilizing the protein shape. 22) The region at codons 83-92 has been suggested to be involved in the initial stage of folding of the monomer, 23) and the regions at the N-and C-termini play a role in maintaining the stability of the dimerization interface. 22) HXB2 is one of the most major wild-type strains of HIV-1 and it has been employed in many experimental studies.…”

“…22) The region at codons 83-92 has been suggested to be involved in the initial stage of folding of the monomer, 23) and the regions at the N-and C-termini play a role in maintaining the stability of the dimerization interface. 22) HXB2 is one of the most major wild-type strains of HIV-1 and it has been employed in many experimental studies. 24) Hence, the sequence of this strain was used as a principal reference of HIV-1 protease in this work.…”

Flexibility and extracellular opening determine the interaction between ligands and insect sulfakinin receptors

“…The normal mode vibrations are harmonic oscillations characterizing the dynamics of the system around a minimum energy. In this case, each mode describes a state of the system where all particles are oscillating with the same characteristic frequency 23 24 . The NMA technique is based on a quadratic approximation of the potential energy surface and the equation of motion is solved analytically and its results are obtained in terms of directions of movements with their respective frequencies.…”

Synthetic lethals in HIV: ways to avoid drug resistance

“…However, the active site is not the only essential part of a protein as this function is carried by its threedimensional structure. Protease studies [33] show that its very flexible structure allows the flaps to open in order to accommodate its substrate. It is obvious that opening the flaps is an essential function for the enzymatic activity.…”

“…3. r 2 [41] is an index derived from the correlation index D Lewontin [39,13,40]. Using recoding alignments, this test r 2 has been computed in Perl according to (13,32,33) for all pairs of positions variants and accessible. The pairs corresponding to these p-values are black on the heatmap of Figure 1 and numbered in the green area on Figure 2 for RT.…”