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Protein sequences serve as a natural record of the evolutionary constraints that shape their functional structures. We show that it is possible to use only sequence information to go beyond predicting native structures and global stability to infer the folding mechanisms of globular proteins. The one- and two-body evolutionary energy fields at the amino-acid level are mapped to a coarse-grained description of folding, where proteins are divided into contiguous folding elements, commonly referred to as foldons.

Mosquito-borne flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), constitute a significant and escalating public health threat. Elucidating the mechanisms by which these flaviviruses subvert cellular processes through viral protein-host cell interactions provides critical insights into their replication and pathogenicity. Here, we present an analysis based on anisotropy calculation across pixels in raster images to investigate differential protein interactions during nucleocytoplasmic shuttling.

Organelles such as mitochondria have characteristic shapes that are critical to their function. Recent efforts have revealed that the curvature contributions of individual lipid species can be a factor in the generation of membrane shape in these organelles. Inspired by lipidomics data from yeast mitochondrial membranes, we used Martini coarse-grained molecular dynamics simulations to investigate how lipid composition facilitates membrane shaping. We found that increasing lipid saturation increases bending rigidity while reducing the monolayer spontaneous curvature.

Concentrated monoclonal antibody (mAb) solutions can allow subcutaneous administration of effective doses of the therapeutic, but for some mAbs this leads to anomalously high viscosities; mAb-mAb association, leading to formation of clusters or gels, is often the driver of such behavior. Statistical mechanical considerations suggest that such association is likely to be dominated by a single binding configuration. In this work we probe the possible molecular origins of this behavior using atomistic molecular simulations of a mAb known to display high viscosity at low salt concentrations.

The generation and propagation of action potentials in neurons relies on the coordinated activation of voltage-dependent sodium and potassium channels. The Kv1 (Shaker) family of potassium channels drives the repolarization phase of the action potential by opening and closing their pore, a process controlled by a voltage sensor domain. However, a molecular description of how the voltage sensor domain drives pore gating has been constrained by a lack of closed-state structures. Here, we present a structural model of the closed Shaker channel that reveals the structural basis of voltage gating.

Single-molecule analysis of atomic force microscopy (AFM) images is a powerful tool for characterizing the structural and conformational properties of proteins, DNA, and protein-DNA complexes, as well as nonbiological molecules, such as polymers. Since the invention of AFM in 1986, significant technical advances have been made, including faster scan speeds and automated image collection and analysis. Deposition methods, however, remain essentially unchanged. Typically, several microliters of the sample are dropped onto a mica surface (unmodified or modified), allowed to spread, rinsed with water, and dried.

Mesenchymal cells navigate the extracellular matrix (ECM) in vivo by processing both its mechanical properties and confinement geometry. Here we develop a multiscale whole-cell theory to investigate cell spreading and migration in two-dimensional (2D) viscoelastic channel confinements of varying width and curvature. Our simulations show that, in straight channels, the cell migration speed depends monotonically on the substrate elastic stiffness, which is otherwise biphasic on an unconfined substrate.

Plasma membranes (PMs) exhibit asymmetry between their two leaflets in terms of phospholipid headgroups, unsaturation, and resulting membrane properties such as packing and fluidity. Lateral heterogeneity, including the formation of lipid domains, is another crucial aspect of PMs with significant biological implications. However, the nature and even the existence of lipid domains in the two leaflets of PMs remain elusive, hindering a complete understanding of the significance of lipid asymmetry.

Human immunodeficiency virus (HIV) infection is believed to occur through the entry of virion into mammalian cells engineered by the interaction of its fusion peptide in particular gp41 with the plasma membranes. Despite having a significant understanding of the biochemical pathways of HIV infection a viable remedy is yet to be achieved. This necessitates the evaluation of peptide-induced microscopic biophysical changes of the host membrane that support viral entry. In this report, we present the first detailed microscopic insights into the mechanisms of gp41-mediated host membrane dehydration and packing regulation, obtained through the combined use of neutron reflectivity and fluorescence microscopy, which together provide high-resolution structural information.

(Biophysical Journal 123, 1984–2000, July 16, 2024)

Biomolecular simulations played a crucial role in advancing our understanding of the complex dynamics in biological systems with applications ranging from drug discovery to the molecular characterization of virus-host interactions. Despite their success, biomolecular simulations face inherent challenges due to the multiscale nature of biological processes, which involve intricate interactions across a wide range of length- and timescales. All-atom (AA) molecular dynamics provides detailed insights at atomistic resolution, yet it remains limited by computational constraints, capturing only short timescales and small conformational changes.