BJ Articles Ahead of Print

The viral protease domain (NS3pro) of dengue virus is essential for virus replication and its cofactor NS2B is indispensable for the proteolytic function. Although several NS3pro-NS2B complex structures have been obtained, the dynamic property of the complex remains poorly understood. Using NMR relaxation techniques, here we found that NS3pro-NS2B exists in both closed and open conformations which are in dynamic equilibrium on a sub-millisecond timescale in aqueous solution. Our structural information indicates that the C-terminal region of NS2B is disordered in the minor open conformation but folded in the major closed conformation.

DNA strand displacement, where a single-stranded nucleic acid invades a DNA duplex, is pervasive in genomic processes and DNA engineering applications. The kinetics of strand displacement have been studied in bulk; however, the kinetics of the underlying strand exchange were obfuscated by a slow bimolecular association step. Here, we use a novel single-molecule Fluorescence Resonance Energy Transfer (smFRET) approach termed the “fission” assay to obtain the full distribution of first passage times of unimolecular strand displacement.

Water dynamics in the hydration layers of biomolecules play crucial roles in a wide range of biological functions. A hydrated protein contains multiple components of diffusional and vibrational dynamics of water and protein, which may be coupled at approximately 0.1-terahertz frequency (10-picosecond timescale) at room temperature. However, the microscopic description of biomolecular functions based on various modes of protein-water-coupled motions remains elusive. A novel approach for perturbing the hydration dynamics in the sub-terahertz frequency range and probing them at the atomic level is therefore warranted.

To understand the transition from inanimate matter to life, we studied a process that directly couples simple metabolism to evolution via natural selection, demonstrated experimentally by Adamala and Szostak (Nat. Chem. 2013, 5, 495–501). In this process, dipeptides synthesized inside precursors of cells promote absorption of fatty acid micelles to vesicles inducing their preferential growth and division at the expense of other vesicles. The process is explained on the basis of coarse-grained molecular dynamics simulations, each extending for tens of microseconds, carried out to model fusion between a micelle and a membrane, both made of fatty acids in the absence and presence of hydrophobic dipeptides.

The motion in the cytosol of microorganisms such as bacteria and yeast has been observed to undergo a dramatic slowing down upon cell energy depletion. These observations have been interpreted as the motion being “glassy”, but whether this notion is useful also for active, motor protein-driven transport in eukaryotic cells is less clear. Here we use fluorescence microscopy of beads in human (HeLa) cells to probe the motion of membrane-surrounded structures that are carried along the cytoskeleton by motor proteins.

Trinucleotide repeat expansion disorders (TRED) are associated with the overexpansion of (CNG) repeats on the genome. mRNA transcripts of sequences with greater than 60 to 100 (CNG) tandem units have been implicated in TRED pathogenesis. In this paper, we develop a diagrammatic theory to study the structural diversity of these (CNG)n RNA sequences. Representing structural elements on the chain’s conformation by a set of graphs and employing elementary diagrammatic methods, we have formulated a renormalization procedure to re-sum these graphs and arrive at a closed-form expression for the ensemble partition function.

Polyunsaturated fatty acids (PUFAs) modify the activity of a wide range of membrane proteins and are increasingly hypothesized to modulate protein activity by indirectly altering membrane physical properties. Among the various physical properties affected by PUFAs, the membrane area expansion modulus (Ka), which measures membrane strain in response to applied force, is expected to be a significant controller of channel activity. Yet the impact of PUFAs on membrane Ka has not been measured previously.

Parkinson’s disease-associated LRRK2 is a multi-domain Ser/Thr kinase that phosphorylates a subset of Rab GTPases to control their effector functions. Rab GTPases are the prime regulators of membrane trafficking in eukaryotic cells. Rabs exert their biological effects by recruitment of effector proteins to subcellular compartments via their Rab-binding domain (RBD). Effectors are modular and typically contain additional domains that regulate various aspects of vesicle formation, trafficking, fusion and organelle dynamics.

Calcium (Ca2+) is a second messenger assumed to control changes in synaptic strength in the form of both long-term depression (LTD) and long-term potentiation (LTP) at Purkinje cell dendritic spine synapses via inositol trisphosphate (IP3) induced Ca2+ release. These Ca2+ transients happen in response to stimuli from parallel fibers (PF) from granule cells and climbing fibers (CF) from the inferior olivary nucleus. These events occur at low numbers of free Ca2+ requiring stochastic single particle methods when modeling them.

Functionally similar IDPs (Intrinsically Disordered Proteins) often have little sequence similarity. This is in stark contrast to folded proteins and poses a challenge for the inverse problem: functional classification of IDPs using sequence alignment. The problem is further compounded due to the lack of structure in IDPs, preventing structural alignment as an alternate tool for classification. Recent advances in heteropolymer theory unveiled a powerful set of sequence patterning metrics bridging molecular interaction with chain conformation.