Evaluating the Performance of a Non-Bonded Cu2+ Model Including Jahn−Teller Effect into the Binding of Tyrosinase Inhibitors

Lucas Sousa Martins,Cláudio Nahum Alves,José Rogério A Silva,Jerônimo Lameira,Hendrik G Kruger

doi:10.3390/ijms21134783

Abstract

Tyrosinase (TYR) is a metalloenzyme classified as a type-3 copper protein, which is involved in the synthesis of melanin through a catalytic process beginning with the conversion of the amino acid l-Tyrosine (l-Tyr) to l-3,4-dihydroxyphenylalanine (l-DOPA). It plays an important role in the mechanism of melanogenesis in various organisms including mammals, plants, and fungi. Herein, we used a combination of computational molecular modeling techniques including molecular dynamic (MD) simulations and the linear interaction energy (LIE) model to evaluate the binding free energy of a set of analogs of kojic acid (KA) in complex with TYR. For the MD simulations, we used a dummy model including the description of the Jahn–Teller effect for Cu2+ ions in the active site of this enzyme. Our results show that the LIE model predicts the TYR binding affinities of the inhibitor in close agreement to experimental results. Overall, we demonstrate that the classical model provides a suitable description of the main interactions between analogs of KA and Cu2+ ions in the active site of TYR.

Highlights

Melanin is present in many organisms where it plays several key roles including photoprotection, thermoregulation, and wound healing
The coefficients of determination (r2) obtained for the linear regression of predicted values versus the observed contributions were equal to 0.93 and 0.94 for linear interaction energy (LIE) model 1 (Figure 8) and model 2, respectively. These results suggest that the standard parameterization and that obtained from the linear fitting procedure (Figure S4) of LIE are both robust methods that reproduce the experimental affinities of TYR inhibitors
We investigated the accuracy of molecular docking and molecular dynamic (MD) simulations in combination with the LIE method on a set of TYR inhibitors

Summary

Introduction

Melanin is present in many organisms where it plays several key roles including photoprotection, thermoregulation, and wound healing. RRoooott--mmeeaann--ssqquuaaree ddeevviiaattiioonn ((RRMMSSDD)) pplloott ooff ttyyrroossiinnaassee ((TTYYRR)) ssyysstteemmss dduurriinngg 1100nnssooff mmooleleccuulalarrddyynnaammicic(M(MDD) )sismimuulalatitoionns.s. As discussed previously, the CuDum model was applied to describe the Cu2+ ions in the catalytic site of TYR, where the introduction of dummy atoms surrounding the metal ion allows suitable capture of both structural and electrostatic effects −5.99 −5.85 −5.73 −5.24 −4.68 l-DOPA: l-3,4-dihydroxyphenylalanine; l-Tyr: l-Tyrosine; TRO: Tropolone; KA: Kojic acid; vdW: Van der Waals; ele: Electrostatic; LIE: Linear interaction energy; EXP: Experimental. The coefficients of determination (r2) obtained for the linear regression of predicted values versus the observed contributions were equal to 0.93 and 0.94 for LIE model 1 (Figure 8) and model 2, respectively These results suggest that the standard parameterization (model 1) and that obtained from the linear fitting procedure (model 2) (Figure S4) of LIE are both robust methods that reproduce the experimental affinities of TYR inhibitors. TYRBm—l-Tyr TYRBm—TRO TYRBm—KA TYRBm—KA1 TYRBm—KA2 TYRBm—KA3 TYRBm—KA4 TYRBm—KA5

Molecular Docking Simulations

Conclusions