In silico modeling of the molecular structure and binding of leukotriene A4 into leukotriene A4 hydrolase

TL;DR

This study uses in silico molecular modeling and docking to analyze the structure and binding interactions of leukotriene A4 with its hydrolase enzyme, providing insights into their molecular conformations and interactions.

Contribution

It presents a detailed computational approach combining DFT calculations and docking to model leukotriene A4 and its interaction with LTA4 hydrolase, which is novel in this context.

Findings

Identified stable conformations of leukotriene A4 and leukotriene B4.

Proposed a binding model consistent with experimental data.

Analyzed protonation states and their effects on binding.

Abstract

A combined molecular docking and molecular structure in silico analysis on the substrate and product of leukotriene A4 hydrolase (LTA4H) was performed. The molecular structures of the substrate leukotriene A4 (LTA4) and product leukotirene B4 (LTB4) were studied through Density Functional Theory (DFT) calculations at the B3LYP/6-31+G(d) level of theory in both, gas and condensed phases. The whole LTB4 molecule was divided into three fragments (hydrophobic tail, triene motif, and a polar acidic group) which were subjected to a full conformational study employing the most stable conformations of them to build conformers of the complete molecule and geometry optimize further. LTA4 conformers structures were modeled from the LTB4 minimum energy conformers. Both, protonated and deprotonated species of LTA4 and LTB4, were analyzed according to pKa values founded in the literature. Finally, a binding model of LTA4 with LTA4 hydrolase is proposed according to docking results which show intermolecular interactions that position the protonated and deprotonated ligand in the active site, in excellent agreement with experimental data.