Semiempirical methods do Fukui functions: Unlocking a modeling framework for biosystems.

Abstract

Obtaining reactivity information from the molecular electronic structure of a chemical system is a computationally intensive process. As a way of probing reactivity information around that, there exist electron density response variables, such as the Fukui functions (FFs), which are well-established descriptors that summarize the local susceptibility to react. These properties only require few single-point quantum chemical calculations, but even then, the intrinsic high cost and unfavorable computational complexity with respect to the number of atoms in the system makes this approach available only to small fragments and systems. In this study, we explore the computation of FFs, showing that semiempirical quantum chemical methods can be used to obtain the reactivity information equivalent to that of a Density Functional Theory (DFT) functional, for the eight entire polypeptide chains. The combination of semiempirical methods with the frozen orbital approximation allows for the obtention of these reactivity descriptors for biological systems with reasonable accuracy and speed, unlocking the utilization of these methods for such systems. These results for the frozen orbital approximation can be additionally improved when other molecular orbitals from the frontier band are employed in the computation. We also show the potential of this computational protocol in the ligand-protein complexes of HIV-1 protease, predicting which of those ligands are active inhibitors.