Introduction

The antiretroviral chemotherapy helps to reduce the mortality of HIVs infected patients. However, dependent RNA 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.

Objectives

The objective of this study is to investigate structural changes in the HIV-1 protease using a normal modes approach and to correlate the results with drug scape rates.

Methodology

The investigation of protein flexibility may be important for the study of processes associated with conformational changes and state transitions of molecules. The normal mode analysis allowed us to investigate structural changes in the Protease (such as Flexibility) 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 and separately.

Results

These positively selected mutations set significant flexibility changes in important regions such as active site cavity and flaps. These mutations were also able to cause changes in Accessible Solvent Area. This study verified that the majority of HIV-1 Protease mutants can be clustered into mainly two classes of protein flexibility behavior.

Conclusions

We presented a new methodology to study structural changes caused by positively selected mutation in pathogen protein and their applications are known and well established, for example: HIV-1 protease. The method can be applied to any pathogen proteins pharmaceutically relevant and could be very useful to understand the effects of positively selected mutations in structural changes context.