Simulations of the optical activity of voltage sensitive probes in polarized model membranes

GALASSI, VANESA V.; SOSA, MICAELA; DEL PÓPOLO, MARIO

San Luis

Congreso; XLVIII Reunión Anual de la Sociedad Argentina de Biofísica; 2019

Universidad Nacional de San Luis - Sociedad Argentina de Biofísica

Voltage sensitive dyes (VSD) are widely used to determine membrane potential both in imagingdiagnosis field and in scientific research. However, their application is limited by their sensibilityand rate of response [1].We are developing a thorough computational study of optically active molecules sensitive tomembrane potential. As sample cases, we chose di-3-ANEPPDHQ, widely used for in vitrodeterminations [2]; and indocyanine green (ICG), an infrared fluorescent dye with FDA approvalfor medical use [3]. The mechanism of response of these chromophores is basically electrochromic,i.e. the stationary electronic states responsible for the optical activity (light absorbance andfluorescence emission) are sensitive to the external electric field. Thus, the challenge in this kind ofstudy is to combine the electronic description of the dye, prohibitive over a couple of hundredsatoms, with the complex condensed phase of biological systems, which is in turn determinant of theexternal field.We built atomistic models for the probes embedded in polarized membrane bilayers, and performedenhanced sampling calculations to determine the potential of mean force for membrane insertion, inorder to establish the energetics of the partition process and to deconvolute the configurationalcontribution to the optical response.We appealed to the time-dependent resolution of Kohn-Sham equations (TD-DFT) and hybridpotentials from quantum mechanics and molecular mechanics (QM/MM) to calculate the absorptionspectra of the VSDs. We obtained the spectral shifts corresponding to different configurations of thedye in the bilayer: adsorbed and inserted, and differential response to the transmembrane potential.The long-term objective is to develop a methodology that allows the study and optimization ofCSVs.References:[1] L. Loew, Membrane Potential Imaging in the Nervous System: Methods and Applications (Springer-Verlag New York, 2010).[2] J. A. Fisher, et al. , Journal of neurophysiology 99 , 1545 (2008).[3] J. S. Treger, M. F. Priest, R. Iezzi, F. Bezanilla, Biophysical journal 107, L09 (2014).Aknowledgements: CONICET and ANPCyT are aknowledged for funding, and National System of High Performance Computing(SNCAD) for disponibilizing the computational resources used in this work, mainly clusters Toko and Mendieta.