Uso de métodos DFT e de docking molecular para avaliar a quelação de átomos de Ferro em grupos [Fe4S4(Cys)4]-2

Abstract

This work aims to perform a critical analysis of the ability of molecular docking methods to describe electronic interactions in metalloenzymes containing [4Fe–4S] clusters. The study employs Density Functional Theory (DFT) calculations and docking simulations to investigate systems in which metal–ligand interactions require explicit consideration of electronic effects, which are often neglected by classical methods. The methodology initially involved DFT calculations on [4Fe–4S] cluster models coordinated by cysteine residues to evaluate the energetic favorability of ligand coordination. Subsequently, docking studies were carried out on different protein systems using AutoDock4, LeDock, AutoDock Bias, and Metalloprotein Bias Docking, under RESP and AM1-BCC partial charge schemes, in addition to cavity analyses to assess site accessibility. The results demonstrate that, although the search algorithms generate poses with low RMSD values in redocking protocols, the scoring functions consistently fail to reproduce realistic coordination geometries. Excessively short metal–oxygen distances and incorrect orientations of coordinating atoms were favored, regardless of the applied bias or charge scheme. It is concluded that the main limitations of classical docking methods in metalloprotein systems are intrinsically associated with deficiencies in the scoring functions.