ORIGINAL PAPER Molecular modeling of immersion optical clearing of biological tissues Kirill V. Berezin 1 & Konstantin N. Dvoretski 2 & Maria L. Chernavina 1 & Anatoliy M. Likhter 3 & Vladimir V. Smirnov 3 & Ilmira T. Shagautdinova 3 & Ekaterina M. Antonova 3 & Ekaterina Yu. Stepanovich 3 & Elena A. Dzhalmuhambetova 3 & Valery V. Tuchin 1,4,5 Received: 30 May 2017 /Accepted: 8 January 2018 # Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract The interaction of six low-molecular tissue-clearing agents (1,2 and 1,3-propanediol, ethylene glycol, glycerol, xylitol, sorbitol) with the collagen mimetic peptide (GPH) 3 was studied by applying the methods of classical molecular dynamics (GROMACS), molecular docking (AutoDock Vina) and quantum chemistry (PM6 and B3LYP). The spatial configurations of intermolecular complexes were determined and interaction energies calculated. The dependence of the volume occupied by the collagen peptide on the clearing agent concentration in an aqueous solution was calculated. This dependence is not linear, and has a maximum for almost all the agents in the study. The correlations between the optical clearing potential and intermolecular interactions param- eters, such as the time of an agent being in a hydrogen-bonded state, and the relative probability of formation of double hydrogen bonds and interaction energies, were determined. Using the correlations determined, we predicted the numeric value of the optical clearing potential of dextrose molecules in rat skin, which correlates with experimental data. A molecular mechanism of tissue optical clearing within the post-diffusion stage is suggested. Keywords Tissue molecular structure . Tissue optical clearing . Molecular dynamics . Modeling . Hydrogen binding Introduction The application of advanced methods of biomedical optical imaging and phototherapy to diagnose and cure diseases is limited because of strong light scattering in the visible and near infrared region by the skin and underlying tissues. This scattering occurs due to non-uniformity of the index of refrac- tion at the borders of various macromolecular structures, mainly on the collagen fibers that are mostly responsible for light scattering in the skin dermis [1]. To overcome problems with high scattering, impregnation of a tissue with a biocom- patible molecular agent that leads to a decrease in the scatter- ing coefficient and corresponding enhancement of tissue op- tical transmittance is often used [1–5]. Reports of many ex- perimental in vitro and in vivo studies on optical clearing of different types of biological tissues and liquids are available in the literature [1–14]. Tissue optical clearing is currently one of the hot topics in biomedical optical imaging and spectroscopy. Application of this robust technology has been demonstrated in human, rat, and porcine skin [1, 8, 9, 12–14], human dura mater [6], rabbit eye sclera [7], human and porcine cranial bone [10], intralipid [11] and blood [2, 3]. Different optical clearing agents (OCAs) such as sugar alcohols (ethylene gly- col [1], 1,2- propanediol [1, 10, 11], 1,3- propanediol [1], 1,4- butanediol [11], glycerol [1, 9–11]; xylitol [1]; sorbitol [1]; mannitol [6] and polyethylene glycol [11]) and sugars (su- crose; dextrose; fructose [1] and glucose [7, 8, 12]) have been used widely to demonstrate tissue optical clearing with vari- ous efficiencies. All these studies show the urgent interest in this problem. In particular, a book chapter by Bashkatov [15] offers mathematical model of optical clearing in tissues by * Konstantin N. Dvoretski dcn@yandex.ru 1 Department of Optics and Biophotonics, Saratov State University, 83 Astrakhanskaya Street, Saratov 410012, Russia 2 Department of Medical and Biological Physics, Saratov State Medical University, 112 Bolshaya Kazachya Street, Saratov 410012, Russia 3 Department of General Physics, Astrakhan State University, 20A Tatishcheva Street, Astrakhan 414056, Russia 4 Institute of Precision Mechanics and Control, Russian Academy of Sciences, 24 Rabochaya Street, Saratov 410028, Russia 5 Interdisciplinary Laboratory of Biophotonics, Tomsk State University, 36 Lenin Avenue, 634050 Tomsk, Russia Journal of Molecular Modeling (2018) 24:45 https://doi.org/10.1007/s00894-018-3584-0