Computational screening of cryoprotective agents for regenerative medical products using quantum chemistry and molecular dynamics simulations

Abstract

Cryoprotective agents (CPAs) are essential for the cryopreservation of cells. Thus far, dimethyl sulfoxide (DMSO) has been widely used as a CPA; however, DMSO is known to be toxic to cells. The damaged cells by the toxicity can present abnormal conditions, and should not be used for regenerative medical products because the cells/products are implanted directly into human bodies. With the aim of searching for an alternative CPA to DMSO, this work presents a computational screening of CPA candidate compounds using quantum chemistry and molecular dynamics (MD) simulations. Forty compounds were evaluated in regard to the solvation free energy and partition coefficient by quantum chemistry simulation and the root mean square deviation (RMSD) of a phospholipid bilayer which composes a cell membrane by MD simulation. The solvation free energy, partition coefficient, and RMSD were defined as indicators of osmoregulatory ability, affinity with a cell membrane, and ability to spread a cell membrane, respectively. The quantum chemistry simulation elucidated that the six compounds of trimethylglycine, formamide, urea, thiourea, diethylene glycol, and dulcitol were better than DMSO in either or both of the physical properties considered. This finding is based on the inherent physical property and is thus case-independent. Further characterization with the MD simulation suggested that formamide, thiourea, and urea should be the first candidates to investigate, although the result was valid only in the simulated condition. This work serves as the first step of multi-faceted computational evaluation of multiple compounds in the search for an effective CPA compound after DMSO.