ORIGINAL PAPER Geometric distortions on a three-coordinated T1 Cu site model as a potential strategy to modulate redox potential. A theoretical study Hugo Vázquez-Lima & Patricia Guadarrama & Claudia Martínez-Anaya Received: 3 August 2010 / Accepted: 22 March 2011 / Published online: 4 May 2011 # Springer-Verlag 2011 Abstract A model of the three-coordinated T1 Cu site from Trametes versicolor was considered to evaluate the effect on redox potential of geometrical distortions in the copper coordination sphere. Systematic modifications of geometrical parameters (distances and angles) of the coordination sphere of the T1 Cu site were carried out within a density functional theory (DFT) framework, to evaluate their effects on electron affinity directly related to redox potential. The most promising result in terms of redox potential increment was distortion of the dihedral angle C methylthiolate –S–Cu–N ImA (ω), which can be rationalized as a decrease in the overlap of imidazole orbitals in the redox-active molecular orbital (β-LUMO). This overlap is minimized when ω achieves the value of 10°, therefore, this conformation might have the highest redox potential. From the molecular orbital viewpoint, a parallelism was found between the effect caused by the presence of a fourth ligand and the distorted three-coordination, which could be extrapolated to spectroscopic properties. It was also found that solvation effects on the redox potentials during geometrical distortions produce a very similar tendency, independently of the polarity of the solvent. Keywords Density functional theory . Laccase . Redox potential . Enzymatic model Introduction Laccases are enzymes belonging to a family known as multicopper oxidases containing four copper atoms classified in three different types (T1, T2, and T3), according to their spectroscopic properties in oxidized state [Cu (II)] [1]. These enzymes have an enormous biotechnological potential in environmental remediation since they are able to catalytically oxidize several harmful substrates such as phenols and aromatic amines. The accepted mechanism involves a first stage where Cu (II) in the T1 Cu site is reduced to Cu (I), and this active site is then re-oxidized with the concomitant reduction of O 2 to H 2 O[2]. Nowadays, there is a growing interest in understanding the complex mechanisms involved in the activity of laccases and, at the same time, there is a constant search for new varieties of laccases with higher stability and higher redox potential to cover a wider spectrum of substrates [3]. The T1 Cu, responsible for the blue color of these enzymes when oxidized [4], has been studied extensively, and is a recurrent motif found in proteins involved in redox processes. This copper atom is surrounded by two histidine (His) and one cysteine (Cys) residues, all of which are conserved in all T1 Cu sites. A fourth residue can be methionine (Met), glutamine (Gln), leucine (Leu), isoleucine (Ile) or phenylalanine (Phe), depending on the protein. In most proteins, the T1 Cu site is directly responsible for the redox potential, which is modulated by five factors: (1) the number of copper coordinated residues [lower coordination numbers of Cu (II) destabilized this state, resulting in higher redox potentials], (2) distortions in the Electronic supplementary material The online version of this article (doi:10.1007/s00894-011-1063-y) contains supplementary material, which is available to authorized users. H. Vázquez-Lima : P. Guadarrama (*) Instituto de Investigaciones en Materiales, Universidad Nacional Autónoma de México, Apartado Postal 70–360, CU, Coyoacán, Mexico DF 04510, Mexico e-mail: patriciagua@iim.unam.mx C. Martínez-Anaya Departamento de Ingeniería Celular y Biocatálisis, Instituto de Biotecnología (IBT), Universidad Nacional Autónoma de México, Av. Universidad 2001, Col. Chamilpa, 62250 Cuernavaca, Morelos, Mexico J Mol Model (2012) 18:455–466 DOI 10.1007/s00894-011-1063-y