ELECTRONIC DISLOCATION IN PROTEINS: CHARACTERIZATION OF ELECTRONIC STRUCTURE AT ENZYMATIC REACTION SITES

Electronic delocalization, especially of π electrons, is a determining factor for the structural stability and reactivity of biomolecules. In proteins, this phenomenon occurs predominantly between peptide bonds. In enzymes, electronic delocalization contributes to the stabilization of transition states in the active site, directly influencing catalytic efficiency and specificity in interactions with ligands and substrates. This project aims to investigate electronic delocalization within an enzymatic context and its relevance for molecular recognition mechanisms. Computational chemistry methods were used at two main levels: (i) in model peptides of composition H₃C–Gly₅–X–Gly₅–CH₃, varying the central amino acid (X); and (ii) in selected enzymes. Polyglycine polymers were modeled using Avogadro (v1.95) with initial geometric optimization by the UFF force field. Systems with varied central residues were constructed via the Molefacture plugin in VMD (v1.9.4a55) and subsequently optimized using the semiempirical PM6-D3H4 BFGS method in MOPAC2016. Quantum mechanics calculations were performed with ORCA (v5.0.4) using density functional theory (DFT) at the B3LYP/6-31G* level. For enzymatic systems, hybrid QM/MM simulations are currently performed using the NAMD (v2.14) interface with ORCA (v5.0.4). The classical region is modeled with the CHARMM36 force field, while the quantum region employs DFT B3LYP/6-31G*. This approach enables detailed analysis of the electronic distribution in catalytic sites at the atomic scale, elucidating its influence on catalytic mechanisms and ligand interactions. The substitution of the central residue in polyglycine polymers alters the electronic delocalization pattern according to physicochemical characteristics. Nonpolar polymers exhibit orbitals extensively delocalized along the chain; polar polymers localize orbitals largely at the HOMO level; negatively charged polymers concentrate orbitals mainly at the HOMO level; positively charged polymers localize orbitals predominantly at the LUMO level; and aromatic polymers exhibit orbitals dispersed across both energy bands. This information contributes to understanding electronic factors modulating enzymatic activity and guides rational strategies for designing selective drugs and enzyme inhibitors.