Kovalskyy D. Effect of Distal Mutations on Conformational Behavior of HIV-1 Protease: Molecular Dynamics Simulations Study.

The moceular dynamics simulation technique was used to perform the systamatic investigation of the conformational behavior of native HIV-1 at different enviromant conditions and to study the effect of distal mutations L10I, L90M, A71V/G73S/I93L та E35Q/M36I/S37D/R57K on its conformational dynamics as mechanism of drug resistance. It is shown that the structural stability of the protease dimer is largely depend on the protonation state of the catalytic dyad Asp25/25'. Is it established the existance of two mechanisms of the effect of distal mutations on MD of HIV-1 protease -- through the redistribution of its correlated motions and through the changes of the available conformational motions of the enzyme. The algorithm to compare NMR and MD derived data is developed. The algorithm to compare dynamical characteristics of two proteins is developed. Results of the study could be used to design inhibitors of HIV-1 protease of new generation that will be active against native as well as certain drug resistant types of the enzyme.