ABSTRACT
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.
ABSTRACT
The lipid dynamics and phase play decisive roles in drug encapsulation and delivery to the intracellular target. Thus, understanding the dynamic and structural alterations of membranes induced by drugs is essential for targeted delivery. To this end, united-atom molecular dynamics simulations of a model bilayer, dioctadecyldimethylammonium bromide (DODAB), are performed in the absence and presence of the usual nonsteroidal anti-inflammatory drug (NSAID), aspirin, at 298, 310, and 345 K. At 298 and 310 K, the bilayers are in the interdigitated two-dimensional square phases, which become rugged in the presence of aspirin, as evident from height fluctuations. At 345 K, the bilayer is in the fluid phase in both the absence and presence of aspirin. Aspirin is preferentially located near the oppositely charged headgroup and creates void space, which leads to an increase in the interdigitation and order parameters. Although the center of mass of lipids experiences structural arrest, they reach the diffusive regime faster and have higher lateral diffusion constants in the presence of aspirin. Results are found to be consistent with recent quasi-elastic neutron scattering studies that reveal that aspirin acts as a plasticizer and enhances lateral diffusion of lipids in both ordered and fluid phases. Different relaxation time scales of the bonds along the alkyl tails of DODAB due to the multitude of lipid motions become faster upon the addition of aspirin. Our results show that aspirin insertion is most favorable at physiological temperature. Thus, the ordered, more stable, and faster DODAB bilayer can be a potential drug carrier for the protected encapsulation of aspirin, followed by targeted and controlled drug release with antibacterial activity in the future.
