Simulations of Reactive Processes in Complex Biological Systems

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

Mendoza

Simposio; II Simposio de Medicina Traslacional; 2019

Facultad de Ciencias Médicas - Universidad Nacional de Córdoba

p { margin-bottom: 0.1in; line-height: 120%; }IntroductionSimulationof reactive processes require an electronic description of thesystem, prohibitive over a couple of hundreds atoms, as it is thecase of biological systems. For this reason, multi-scale methodsbased in QM/MM hybrid potentials emerge as an attractive alternativeto simulate supra and macromolecular systems such as biologicalmembranes and protein catalysts. We apply this methodology in twosample cases: i) simulation of the optical response of membranepotential sensitive dyes (VSD), potentially useful in braindiagnostic methods; and ii) calculation of the energetics of theproton coupled electron transfer (PCET) in cytochrome bc1, essentialto photosynthetic and cellular respiration processes and whosefailure is determinant in several mitochondrial diseases.MethodsWeappeal to the time-dependent and time-independent resolution ofKohn-Sham equations (TD-DFT) and QM/MM potentials to calculate: i)absorption spectra of di-3-ANEPPDHQ inserted or absorbed in DPPClipid membranes with and without polarization; and ii) calculation ofthe energy in the PCET from ubiquinone cofactor (UH6) to theRieske-type [2Fe-2S] cluster involved in the rate determinant step ofthe Q-cycle, which takes place at the oxidation site (Qo) ofCytocrome bc1 integrated in POPC membranes.Resultsi)We obtained the spectral shifts corresponding to differentconfigurations of the dye in the bilayer: adsorbed and inserted, anddifferential response to the transmembrane potential.ii)We calculated therelative energy profiles for PCET from UH6 to His152 of Rieskesubunit for several configurations from molecular dynamicssimulations of cytochrome bc1. They display the variability typicalfrom rugged potential surfaces of condensed-phase reactions, and afavorable enthalpy of oxidation by 20-50 kJ/mol. Electron transfercould be monitored along the proton transfer scan.ConclusionsTheapplication of multi-scalemethods has enabled us toobtain electronic propertiesin condensed phase andcorrelationsconfiguration-electron redistribution/opticalresponse couldbe drawn.