Interface Water Assists in Dimethyl Sulfoxide Crossing and Poration in Model Bilayer

Understanding the mechanism of transport and pore formation by a commonly used cryoprotectant, dimethyl sulfoxide (DMSO), across cell membranes is fundamentally crucial for drug delivery and cryopreservation. To shed light on the mechanism and thermodynamics of pore formation and crossing behavior of DMSO, extensive all-atom molecular dynamics simulations of 1,2-dimyristoyl-rac-glycero-3-phosphocholine (DMPC) bilayers are performed at various concentrations of DMSO at a temperature above the physiological temperature. Our results unveil that DMSO partially depletes water from the interface and positions itself between lipid heads without full dehydration. This induces a larger area per headgroup, increased disorder, and enhanced fluidity without any disintegration even at the highest DMSO concentration studied. The enhanced disorder fosters local fluctuations at the interface that nucleate dynamic and transient pores. The potential of mean force (PMF) of DMSO crossing is derived from two types of biased simulations: a single DMSO pulling using the umbrella sampling technique and a cylindrical pore formation using the recently developed chain reaction coordinate method. In both cases, DMSO crossing encounters a barrier attributed to unfavorable polar nonpolar interactions between DMSO and lipid tails. As the DMSO concentration increases, the barrier height reduces along with the faster lateral and perpendicular diffusion of DMSO suggesting favorable permeation. Our findings suggest that the energy required for pore formation decreases when water assists in the formation of DMSO pores. Although DMSO displaces water from the interface toward the far interface region without complete dehydration, the presence of interface water diminishes pore formation free energy. The existence of interface water leads to the formation of a two-dimensional percolated water-DMSO structure at the interface, which is absent otherwise. Overall, these insights into the mechanism of DMSO crossing and pore formation in the bilayer will contribute to understanding cryoprotectant behavior under supercooled conditions in the future.