BJ Articles Ahead of Print

Heterochromatin protein 1 (HP1), associated with heterochromatin formation, recognizes an epigenetically repressive marker, trimethylated lysine 9 in histone H3 (H3K9me3), and generally contributes to long-term silencing. How HP1 induces heterochromatin is not fully understood. Recent experiments suggested that not one, but two nucleosomes provide a platform for this recognition. Integrating previous and new biochemical assays with computational modeling, we provide near-atomic structural models for HP1 binding to the dinucleosomes.

Bacteria are microorganisms central to health and disease, serving as important model systems for our understanding of molecular mechanisms and for developing new methodologies and vehicles for biotechnology. In the past few years, our understanding of bacterial cell functions has been enhanced substantially by powerful single-molecule imaging techniques. Using single fluorescent molecules as a means of breaking the optical microscopy limit, we can now reach resolutions of ∼20 nm inside single living cells, a spatial domain previously accessible only by electron microscopy.

In eukaryotic chromatin, islands of histone tail acetylation are found near transcription start sites and enhancers, whereas linker histones (LHs) are localized in intergenic regions with wild-type (WT) histone tails. However, the structural mechanisms by which acetylation, in combination with LH binding, modulates chromatin compaction and hence transcription regulation are unknown. To explore the folding propensity by which these features may govern gene expression, we analyze 20 kb fibers that contain regularly spaced acetylation islands of two sizes (2 or 5 kb) with various LH levels by mesoscale modeling.

Amyloid fibrils are stable aggregates of misfolded proteins and polypeptides that are insoluble and resistant to protease activity. Abnormal formation of amyloid fibrils in vivo may lead to neurodegenerative disorders and other systemic amyloidosis, such as Alzheimer’s, Parkinson’s, and atherosclerosis. Because of their clinical importance, amyloids are under intense scientific research. It is believed that short polypeptide segments within proteins are responsible for the transformation of correctly folded proteins into parts of larger amyloid fibrils and that this transition is modulated by environmental factors, such as pH, salt concentration, interaction with the cell membrane, and interaction with metal ions.

Listeria monocytogenes is an intracellular food-borne pathogen that has evolved to enter mammalian host cells, survive within them, spread from cell to cell, and disseminate throughout the body. A series of secreted virulence proteins from Listeria are responsible for manipulation of host-cell defense mechanisms and adaptation to the intracellular lifestyle. Identifying when and where these virulence proteins are located in live cells over the course of Listeria infection can provide valuable information on the roles these proteins play in defining the host-pathogen interface.

The dynamics of biomolecules in the plasma membrane is of fundamental importance to understanding cellular processes. Cellular signaling often starts with extracellular ligand binding to a membrane receptor, which then transduces an intracellular signal. Ligand binding and receptor-complex activation often involve a complex rearrangement of proteins in the membrane, which results in changes in diffusion properties. Two widely used methods to characterize biomolecular diffusion are single-particle tracking (SPT) and imaging total internal reflection fluorescence correlation spectroscopy (ITIR-FCS).

The composition and electrolyte concentration of the aqueous bathing environment have important consequences for many biological processes and can profoundly affect the behavior of biomolecules. Nevertheless, because of computational limitations, many molecular simulations of biophysical systems can be performed only at specific ionic conditions: either at nominally zero salt concentration, i.e., including only counterions enforcing the system’s electroneutrality, or at excessive salt concentrations.

Nanoparticles used in cellular applications encounter free serum proteins that adsorb onto the surface of the nanoparticle, forming a protein corona. This protein layer controls the interaction of nanoparticles with cells. For nanomedicine applications, it is important to consider how intravenous injection and the subsequent shear flow will affect the protein corona. Our goal was to determine if shear flow changed the composition of the protein corona and if these changes affected cellular binding.

Chromatin is partitioned on multiple length scales into subcompartments that differ from each other with respect to their molecular composition and biological function. It is a key question how these compartments can form even though diffusion constantly mixes the nuclear interior and rapidly balances concentration gradients of soluble nuclear components. Different biophysical concepts are currently used to explain the formation of “chromatin bodies” in a self-organizing manner and without consuming energy.

The mechanism by which the “beads-on-a-string” nucleosome chain folds into various higher-order chromatin structures in eukaryotic cell nuclei is still poorly understood. The various models depicting higher-order chromatin as regular helical fibers and the very opposite “polymer melt” theory imply that interactions between nucleosome “beads” make the main contribution to the chromatin compaction. Other models in which the geometry of linker DNA “strings” entering and exiting the nucleosome define the three-dimensional structure predict that small changes in the linker DNA configuration may strongly affect nucleosome chain folding and chromatin higher-order structure.

The compact structure of the nucleosome limits DNA accessibility and inhibits the binding of most sequence-specific proteins. Nucleosomes are not randomly located on the DNA but positioned with respect to the DNA sequence, suggesting models in which critical binding sites are either exposed in the linker, resulting in activation, or buried inside a nucleosome, resulting in repression. The mechanisms determining nucleosome positioning are therefore of paramount importance for understanding gene regulation and other events that occur in chromatin, such as transcription, replication, and repair.

Ensemble docking corresponds to the generation of an “ensemble” of drug target conformations in computational structure-based drug discovery, often obtained by using molecular dynamics simulation, that is used in docking candidate ligands. This approach is now well established in the field of early-stage drug discovery. This review gives a historical account of the development of ensemble docking and discusses some pertinent methodological advances in conformational sampling.