The detailed organization of cellular membranes remains rather elusive. Based on large-scale molecular dynamics simulations, we provide a high-resolution view of the lipid organization of a plasma membrane at an unprecedented level of complexity. Our plasma membrane model consists of 63 different lipid species, combining 14 types of headgroups and 11 types of tails asymmetrically distributed across the two leaflets, closely mimicking an idealized mammalian plasma membrane. We observe an enrichment of cholesterol in the outer leaflet and a general non-ideal lateral mixing of the different lipid species. Transient domains with liquid-ordered character form and disappear on the microsecond time scale. These domains are coupled across the two membrane leaflets. In the outer leaflet, distinct nanodomains consisting of gangliosides are observed. Phosphoinositides show preferential clustering in the inner leaflet. Our data provide a key view on the lateral organization of lipids in one of life's fundamental structures, the cell membrane.

Computational modeling of biological systems is challenging because of the multitude of spatial and temporal scales involved. Replacing atomistic detail with lower resolution, coarse grained (CG), beads has opened the way to simulate large-scale biomolecular processes on time scales inaccessible to all-atom models. We provide an overview of some of the more popular CG models used in biomolecular applications to date, focusing on models that retain chemical specificity. A few state-of-the-art examples of protein folding, membrane protein gating and self-assembly, DNA hybridization, and modeling of carbohydrate fibers are used to illustrate the power and diversity of current CG modeling.

Major histocompatibility complex (MHC)-E is a highly conserved, ubiquitously expressed, non-classical MHC-Ib molecule with limited polymorphism primarily involved in NK cell regulation. We found that vaccination of rhesus macaques (RM) with ΔRh157.5/.4 Rhesus Cytomegalovirus (RhCMV) vectors results in MHC-E-restricted presentation of highly varied peptide epitopes to CD8α/β+ T cells, approximately 4 distinct epitopes per 100 amino acids in all tested antigens. Computational structural analysis revealed that MHC-E provides heterogeneous chemical environments for diverse side chain interactions within a stable, open binding groove. Since MHC-E is up-regulated on cells infected with HIV/SIV and other persistent viruses to evade NK cell activity, MHC-E-restricted CD8+ T cell responses have the potential to exploit pathogen immune evasion adaptations, a capability that might endow these unconventional responses with superior efficacy.

Gram-negative bacteria are intrinsically resistant to many antibiotics. Species that have acquired multidrug resistance and cause infections that are effectively untreatable present a serious threat to public health. The problem is broadly recognized and tackled at both the fundamental and applied levels. This paper summarizes current advances in understanding the molecular bases of the low permeability barrier of Gram-negative pathogens, which is the major obstacle in discovery and development of antibiotics effective against such pathogens. Gaps in knowledge and specific strategies to break this barrier and to achieve potent activities against difficult Gram-negative bacteria are also discussed.

We present an extension of the Martini coarse-grained force field to carbohydrates. The parametrization follows the same philosophy as was used previously for lipids and proteins, focusing on the reproduction of partitioning free energies of small compounds between polar and nonpolar phases. The carbohydrate building blocks considered are the monosaccharides glucose and fructose and the disaccharides sucrose, trehalose, maltose, cellobiose, nigerose, laminarabiose, kojibiose, and sophorose. Bonded parameters for these saccharides are optimized by comparison to conformations sampled with an atomistic force field, in particular with respect to the representation of the most populated rotameric state for the glycosidic bond. Application of the new coarse-grained carbohydrate model to the oligosaccharides amylose and Curdlan shows a preservation of the main structural properties with 3 orders of magnitude more efficient sampling than the atomistic counterpart. Finally, we investigate the cryo- and anhydro-protective effect of glucose and trehalose on a lipid bilayer and find a strong decrease of the melting temperature, in good agreement with both experimental findings and atomistic simulation studies.