BJ Articles Ahead of Print

A single nucleotide polymorphism, tyrosine 402 to histidine (Y402H), within the gene encoding complement Factor H (FH) predisposes individuals to acquiring age-related macular degeneration (AMD) after aging. This polymorphism occurs in short consensus repeat (SCR) 7 of FH and results in decreased binding affinity of SCR6-8 for heparin. As FH is responsible for regulating the complement system, decreased affinity for heparin results in decreased regulation on surfaces of self. To understand the involvement of the Y402H polymorphism in AMD, we leverage methods from bioinformatics and computational biophysics to quantify structural and dynamical differences between SCR7 isoforms that contribute to decreased pattern recognition in SCR7H402.

The action potential of nerve and muscle is produced by voltage sensitive channels that include a specialized device to sense voltage. The voltage sensor depends on the movement of charges in the changing electric field, as suggested by Hodgkin and Huxley. Gating currents of the voltage sensor are now known to depend on the movements of positively charged arginines through the hydrophobic plug of a voltage sensor domain. Transient movements of these permanently charged arginines, caused by the change of transmembrane potential V, further drag the S4 segment and induce opening/closing of ion conduction pore by moving the S4-S5 linker.

As the journal of the Biophysical Society, the Biophysical Journal serves a diverse and multi-discipline research community of authors and readers. It needs to reflect the mission to publish “[…] work that elucidates important biological, chemical, or physical mechanisms and provides quantitative insight into fundamental problems at the molecular, cellular, and systems and whole-organism levels. Articles published in the Journal should be of general interest to quantitative biologists, regardless of their research specialty.” It is a tall order and one the journal takes seriously.

Metal ions play essential roles in nucleic acids folding and stability. The interaction between metal ions and nucleic acids can be highly complicated due to the interplay between the various effects such as ion correlation, fluctuation, and dehydration. These effects may be particularly important for multivalent ions such as Mg2+ ions. Previous efforts to model ion correlation and fluctuation effects led to the development of the Monte Carlo Tightly Bound Ion (MCTBI) model. Here, by incorporating ion hydration/dehydration effects into the MCTBI model, we develop a new approach to predict ion binding.

Cryo-cooling is routinely performed before X-ray diffraction image collection, to reduce the damage to crystal due to ionizing radiations. It has been suggested that, while backbone structures are usually very similar between room-temperature and cryo-temperature, cryo-cooling may hamper biologically relevant dynamics. In this study, crystal of Escherichia coli dihydrofolate reductase (DHFR) is studied with replica-exchange molecular dynamics simulation and results are compared with crystal structure determined at cryo-temperature and room-temperature with time-averaged ensemble method.

RNA can anneal to its DNA template to generate an RNA–DNA hybrid (RDH) duplex and a displaced DNA strand, termed R-loop. RDH duplex occupies up to 5% of the mammalian genome and plays important roles in many biological processes. The functions of RDH duplex are affected by its mechanical properties including the elasticity and the conformation transitions. The mechanical properties of RDH duplex, however, are still unclear. In this work, we studied the mechanical properties of RDH duplex using magnetic-tweezers in comparisons with those of DNA and RNA duplexes with the same sequences.

Cyclic interactions between myosin II motor domains and actin filaments that are powered by turnover of ATP, underlie muscle contraction and have key roles in motility of non-muscle cells. The elastic characteristics of actin-myosin cross-bridges are central in the force-generating process and disturbances in these properties may lead to disease. Whereas the prevailing paradigm is that the cross-bridge elasticity is linear (Hookean), recent single molecule studies suggest otherwise. Despite convincing evidence for substantial non-linearity of the cross-bridge elasticity in the single molecule work, this finding has had limited influence on muscle physiology and physiology of other ordered cellular actin-myosin ensembles.

The relation between thermal fluctuations and the mechanical response of a free membrane has been explored in great detail, both theoretically and experimentally. However, understanding this relationship for membranes, locally pinned by proteins, is significantly more challenging. Given that the coupling of the membrane to the cell cytoskeleton, the extracellular matrix and to other internal structures is crucial for the regulation of a number of cellular processes, understanding the role of the pinning is of great interest.

Fosfomycin is a frequently prescribed drug in the treatment of acute urinary tract infections. It enters the bacterial cytoplasm and inhibits the biosynthesis of peptidoglycans by targeting the MurA enzyme. Despite extensive pharmacological studies and clinical use, the permeability across the bacterial outer membrane of fosfomycin is largely unexplored. Here, we investigate the fosfomycin permeability across the outer membrane of Gram-negative bacteria by electrophysiology experiments as well as by all-atom molecular dynamics simulations including free energy and applied-field techniques.

The atomic-level mechanisms that coordinate ligand release from protein pockets are only known for a handful of proteins. Here, we report results from accelerated molecular dynamics (aMD) simulations for benzene dissociation from the buried cavity of the T4 lysozyme Leu99Ala mutant (L99A). In these simulations, benzene is released through a previously characterized sparsely populated room temperature excited state of the mutant, explaining the coincidence for experimentally measured benzene off rate and apo protein slow timescale NMR relaxation rates between ground and excited states.

Pore-spanning membranes (PSMs) composed of supported membrane parts (s-PSMs) as well as freestanding membrane parts (f-PSMs) are shown to be very versatile to investigate SNARE-mediated fusion on the single particle level. They provide a planar geometry readily accessible by confocal fluorescence microscopy, which enabled us for the first time to investigate the fusion of individual natural secretory granules – chromaffin granules (CGs) – on the single particle level by two color fluorescence microscopy in a time-resolved manner.

(Biophysical Journal 106, 1751–1762; April 15, 2014)