REACTIVITY PROFILE OF ENZYMES APPLYING QUANTUM MECHANICS CALCULATIONS OVER MICROSSECONDS MOLECULAR DYNAMICS SIMULATIONS AND ANALYSING KEY RESIDUES INFLUENCE THROUGH TIME

Applying Quantum Mechanics (QM) to collect the electronic data of a system of a whole
enzyme in a solvent box is still far from accessible to most of the scientific community
computationally. The use of Semiempirical methods capable of assessing electron density
data including the transfer of charges between the chosen macromolecule and its
surroundings at a faster pace is a more feasible alternative. However, to be able to extract
biological information that arises over bigger time steps such as structural changes in
domains or interaction sites still requires Molecular Dynamics (MD) simulations, since we are
able to reach the microsseconds scale nowadays. This work aims to explore the difference
in the reactivity depending on the conformation of a cysteine protease enzyme from
Plasmodium spp. throughout the dynamics. They were run using the NAMD3 software for 1
μs each replicate, from which 500 spread frames were selected for QM calculations. The self
developed program DescripTraj was used after the simulations to run and extract all the
relevant data presented here. It was possible by MOPAC2016 runs with algorithms PM7 and
MOZYME to obtain the proteic electronic density’s data, then processed by PRIMoRDiA.
Distinct descriptors that account for the system's electrophilicity, nucleophilicity and their
difference were used for assessment of the reactivity of the complete structure of such
enzyme. The results show clearly the variance in the reactivity value of the descriptors
throughout time. It is true not only for a residue but also among its atoms. The reactivity
results, associated with structural motions among the replicates, gave insights on the
participation of residues such as the Tryptophan on the catalytic site and could help us guide
drug development towards that. In conclusion, these findings lead us to believe that changes
in the reactivity profile, which depend on the structure and distance between residues in the
catalytic site, are key to associate and comprehend the big picture on how the evolution has
selected the best composition for a localization of atoms more prone to react with other
molecules.