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

Area of Science:

• Computational Chemistry
• Quantum Chemistry
• Biochemistry

Background:

• Calculating molecular reactivity using electronic structure is computationally demanding.
• Fukui functions (FFs) are established descriptors of local reactivity but are limited to small systems due to high computational cost.

Purpose of the Study:

• To investigate the feasibility of using semiempirical quantum chemical methods for computing FFs in large biological systems.
• To assess the accuracy and efficiency of these methods for predicting reactivity and identifying active inhibitors.

Main Methods:

• Computation of Fukui functions (FFs) using semiempirical quantum chemical methods.
• Application of the frozen orbital approximation for calculating FFs in polypeptide chains.
• Validation of the protocol using ligand-protein complexes of HIV-1 protease.

Main Results:

• Semiempirical methods provide reactivity information comparable to Density Functional Theory (DFT) for entire polypeptide chains.
• The frozen orbital approximation combined with semiempirical methods offers a balance of accuracy and speed for biological systems.
• Improved accuracy was observed when incorporating additional molecular orbitals from the frontier band.
• The protocol successfully predicted active inhibitors among ligands for HIV-1 protease.

Conclusions:

• Semiempirical quantum chemical methods, particularly with the frozen orbital approximation, enable efficient computation of Fukui functions for large biological molecules.
• This approach significantly expands the applicability of reactivity descriptors to complex biological systems.
• The developed computational protocol shows promise for drug discovery, specifically in identifying potential therapeutic agents like HIV-1 protease inhibitors.