The physical properties of lipid bilayers are sensitive to the specific type and composition of the lipids that make up the many different types of cell membranes. Studying model bilayers of representative heterogeneous compositions can provide key insights into membrane functionality. In this work, we use atomistic molecular dynamics simulations to characterize key properties in a number of bilayer membranes of varying composition. We first examine basic properties, such as lipid area, volume, and bilayer thickness, of simple, homogeneous bilayers comprising several lipid types, which are prevalent in biological membranes. Such lipids are then used in simulations of heterogeneous systems representative of bacterial, mammalian, and cancer membranes. Our analysis is especially focused on depth-dependent, transmembrane profiles; in particular, we calculate lateral pressure and dipole potential profiles, two fundamental properties which play key roles in a large number of biological functions.

Membrane permeation depends on fat content, and (permeant) size also matters.

The resistance of pathogens to traditional antibiotics is currently a global issue of enormous concern. As the discovery and development of new antibiotics become increasingly challenging, synthetic antimicrobial lipopeptides (AMLPs) are now receiving renewed attention as a new class of antimicrobial agents. In contrast to traditional antibiotics, AMLPs act by physically disrupting the cell membrane (rather than targeting specific proteins), thus reducing the risk of inducing bacterial resistance. In this study, we use microsecond-timescale atomistic molecular dynamics simulations to quantify the interaction of a short AMLP (C16-KKK) with model bacterial lipid bilayers. In particular, we investigate how fundamental transmembrane properties change in relation to a range of lipopeptide concentrations. A number of structural, mechanical, and dynamical features are found to be significantly altered in a non-linear fashion. At 10 mol% concentration, lipopeptides have a condensing effect on bacterial bilayers, characterized by a decrease in the area per lipid and an increase in the bilayer order. Higher AMLP concentrations of 25 and 40 mol% destabilize the membrane by disrupting the bilayer core structure, inducing membrane thinning and water leakage. Important transmembrane properties such as the lateral pressure and dipole potential profiles are also affected. Potential implications on membrane function and associated proteins are discussed.

The serotonin1A receptor belongs to the superfamily of G protein-coupled receptors (GPCRs) and is a potential drug target in neuropsychiatric disorders. The receptor has been shown to require membrane cholesterol for its organization, dynamics and function. Although recent work suggests a close interaction of cholesterol with the receptor, the structural integrity of the serotonin1A receptor in the presence of cholesterol has not been explored. In this work, we have carried out all atom molecular dynamics simulations, totaling to 3 μs, to analyze the effect of cholesterol on the structure and dynamics of the serotonin1A receptor. Our results show that the presence of physiologically relevant concentration of membrane cholesterol alters conformational dynamics of the serotonin1A receptor and, on an average lowers conformational fluctuations. Our results show that, in general, transmembrane helix VII is most affected by the absence of membrane cholesterol. These results are in overall agreement with experimental data showing enhancement of GPCR stability in the presence of membrane cholesterol. Our results constitute a molecular level understanding of GPCR-cholesterol interaction, and represent an important step in our overall understanding of GPCR function in health and disease.

The response of lipid membranes to changes in external pressure is important for many biological processes, and it can also be exploited for technological applications. In this work, we employ all-atom molecular dynamics simulations to characterize the changes in the physical properties of phospholipid bilayers brought about by high pressure (1000 bar). In particular, we study how the response differs, in relation to different chain unsaturation levels, by comparing monounsaturated 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) and biunsaturated dioleoyl-phosphatidylcholine (DOPC) bilayers. Various structural, mechanical, and dynamical features are found to be altered by the pressure increase in both bilayers. Notably, for most properties, including bilayer area and thickness, lipid order parameters, lateral pressure profile, and curvature frustration energy, we observe significantly more pronounced effects for monounsaturated POPC than biunsaturated DOPC. Possible biological implications of the results obtained are discussed, especially in relation to how different lipids can control the structure and function of membrane proteins.

The human β2-adrenergic receptor (β2AR), a member of the G-protein coupled receptor (GPCR) family, is expressed in bronchial smooth muscle cells. Upon activation by agonists, β2AR causes bronchodilation and relief in asthma patients. The N-terminal polymorphism of β2AR at the 16th position, Arg16Gly, has warranted a lot of attention since it is linked to variations in response to albuterol (agonist) treatment. Although the β2AR is one of the well-studied GPCRs, the N-terminus which harbors this mutation, is absent in all available experimental structures. The goal of this work was to study the molecular level differences between the N-terminal variants using structural modeling and atomistic molecular dynamics simulations. Our simulations reveal that the N-terminal region of the Arg variant shows greater dynamics than the Gly variant, leading to differential placement. Further, the position and dynamics of the N-terminal region, further, affects the ligand binding-site accessibility. Interestingly, long-range effects are also seen at the ligand binding site, which is marginally larger in the Gly as compared to the Arg variant resulting in the preferential docking of albuterol to the Gly variant. This study thus reveals key differences between the variants providing a molecular framework towards understanding the variable drug response in asthma patients.

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