On the reliability of the corrected semiempirical quantum chemical method (PM6-DH2) for assigning the protonation states in HIV-1 protease/inhibitor complexes

Abstract

A novel computational protocol for determining the most probable protonation states in protein/ligand complexes is presented. The method consists in treating large parts of the enzyme using the corrected semiempirical quantum chemical (QM) method – PM6-D2 for optimization and PM6-DH2 for single-point energies – while the rest is calculated using molecular mechanics (MM) within a hybrid QM/MM fashion. The surrounding solvent is approximated by an implicit model. This approach is applied to two model systems, two different carboxylate pairs in one general and one unique HIV-1 protease/inhibitor complex. The effect of the size of the movable QM part is investigated in a series of several sizes, 3-, 6-, 8- and 10-Å regions surrounding the inhibitor. For the smallest region (< 450 atoms) the computationally more costly DFT QM/MM optimizations are performed as a check of the correctness. Proton transfer (PT) phenomena occur at both the PM6-D2 and DFT levels, which underlines the requirement for a QM approach. The barriers of PT are checked in model carboxylic acid pairs using the highly accurate MP2 and CCSD(T) values. An important result of this study is the fine-tuning of the protocol which can be used in further applications; its limitations are also shown, pointing to future developments. The calculations reveal which protonation variants of the active site are the most stable. In conclusion, the presented protocol can also be utilized for defining probable isomers in biomolecular systems. It can also serve as a preparatory step for further interaction-energy and binding-score calculations.