Simulations of Reactive Processes in Complex Biological Systems

MICAELA SOSA; FONROUGE, SERGIO; GALASSI, VANESA; DEL PÓPOLO, MARIO

Mendoza

Simposio; II Simposio de Medicina Traslacional; 2019

Facultad de Ciencias Médicas- Universidad Nacional de Córdoba

Simulation of reactive processes require an electronic description of the system, prohibitive over a couple of hundreds atoms, as it is the case of biological systems. For this reason, multi-scale methods based in QM/MM hybrid potentials emerge as an attractive alternative to simulate supra and macromolecular systems such as biological membranes and protein catalysts. We apply this methodology in two sample cases: i) simulation of the optical response of membrane potential sensitive dyes (VSD), potentially useful in brain diagnostic methods; and ii) calculation of the energetics of the proton coupled electron transfer (PCET) in cytochrome bc1, essential to photosynthetic and cellular respiration processes and whose failure is determinant in several mitochondrial diseases.MethodsWe appeal to the time-dependent and time-independent resolution of Kohn-Sham equations (TD-DFT) and QM/MM potentials to calculate: i) absorption spectra of di-3-ANEPPDHQ inserted or absorbed in DPPC lipid membranes with and without polarization; and ii) calculation of the energy in the PCET from ubiquinone cofactor (UH6) to the Rieske-type [2Fe-2S] cluster involved in the rate determinant step of the Q-cycle, which takes place at the oxidation site (Qo) of Cytocrome bc1 integrated in POPC membranes.Resultsi) We obtained the spectral shifts corresponding to different configurations of the dye in the bilayer: adsorbed and inserted, and differential response to the transmembrane potential.ii) We calculated the relative energy profiles for PCET from UH6 to His152 of Rieske subunit for several configurations from molecular dynamics simulations of cytochrome bc1. They display the variability typical from rugged potential surfaces of condensed-phase reactions, and a favorable enthalpy of oxidation by 20-50 kJ/mol. Electron transfer could be monitored along the proton transfer scan.ConclusionsThe application of multi-scale methods has enabled us to obtain electronic properties in condensed phase and correlations configuration-electron redistribution/optical response could be drawn.