Topological Reaction Coordinate Captures the Folding Transition State Ensemble in a Pierced Lasso Protein.

Proteins with a pierced lasso topology (PLT) have a covalent loop created by a disulfide bond, and the backbone circles back to thread the loop. This threaded topology has unique features compared to knotted topologies; notably, the topology is controlled by the chemical environment and the covalent loop remains intact even when denatured. In this work, we use the hormone leptin as our model PLT system and study its folding using molecular dynamics simulations that employ a structure-based (Go̅-like) model.

Cryo-electron tomography reveals structural insights into the membrane remodeling mode of dynamin-like EHD filaments.

Eps15-homology domain containing proteins (EHDs) are eukaryotic, dynamin-related ATPases involved in cellular membrane trafficking. They oligomerize on membranes into filaments that induce membrane tubulation. While EHD crystal structures in open and closed conformations were previously reported, little structural information is available for the membrane-bound oligomeric form.

Residential substance use treatment outcomes for pregnant and postpartum women: Distinct patterns for women enrolled before versus during the COVID-19 pandemic.

Introduction: Substance use among pregnant and postpartum women (PPW) is a serious public health concern. The COVID-19 pandemic has exacerbated substance use among the general population including pregnant women, and disrupted operations for substance use treatment centers. Little is known about the outcomes of substance use treatment for PPW before and during the COVID-19 pandemic.

SMOG 2 and OpenSMOG: Extending the limits of structure-based models.

Applying simulations with structure-based models has proven to be an effective strategy for investigating the factors that control biomolecular dynamics. The common element of these models is that some (or all) of the intra/inter-molecular interactions are explicitly defined to stabilize an experimentally determined structure. To facilitate the development and application of this broad class of models, we previously released the SMOG 2 software package.

CryoEM structure of the super-constricted two-start dynamin 1 filament.

Dynamin belongs to the large GTPase superfamily, and mediates the fission of vesicles during endocytosis. Dynamin molecules are recruited to the neck of budding vesicles to assemble into a helical collar and to constrict the underlying membrane. Two helical forms were observed: the one-start helix in the constricted state and the two-start helix in the super-constricted state.

Quantification and demonstration of the collective constriction-by-ratchet mechanism in the dynamin molecular motor.

Dynamin oligomerizes into helical filaments on tubular membrane templates and, through constriction, cleaves them in a GTPase-driven way. Structural observations of GTP-dependent cross-bridges between neighboring filament turns have led to the suggestion that dynamin operates as a molecular ratchet motor. However, the proof of such mechanism remains absent.

Don't drink and drive, it's a prime: Cognitive effects of priming alcohol-congruent and incongruent goals among heavy versus light drinkers.

The present experiment assessed implicit alcohol motivations and explicit alcohol expectancies following the interaction between alcohol-congruent (i.e. social drinking) versus incongruent (i.

Not by associations alone: The role of contextual factors, individual differences, and propositional learning in the malleability of implicit alcohol attitudes.

Alcohol attitudes predict unique variance in drinking behavior and have been the target of manipulations and interventions to reduce high-risk alcohol use among youth and adults. However, whether these manipulations create long-lasting changes in alcohol-related attitudes and drinking behavior is unclear. The current mini-review focuses on evaluative conditioning (EC), a manipulation which pairs alcohol-related stimuli repeatedly with affectively valanced stimuli to create new semantic associations in memory; such associations underlie reflexive or impulsive behaviors like high-risk alcohol use.

The Pierced Lasso Topology Leptin has a Bolt on Dynamic Domain Composed by the Disordered Loops I and III.

Leptin is an important signaling hormone, mostly known for its role in energy expenditure and satiety. Furthermore, leptin plays a major role in other proteinopathies, such as cancer, marked hyperphagia, impaired immune function, and inflammation. In spite of its biological relevance in human health, there are no NMR resonance assignments of the human protein available, obscuring high-resolution characterization of the soluble protein and/or its conformational dynamics, suggested as being important for receptor interaction and biological activity.

Polymer-like Model to Study the Dynamics of Dynamin Filaments on Deformable Membrane Tubes.

Peripheral membrane proteins with intrinsic curvature can act both as sensors of membrane curvature and shape modulators of the underlying membranes. A well-studied example of such proteins is the mechanochemical GTPase dynamin, which assembles into helical filaments around membrane tubes and catalyzes their scission in a GTPase-dependent manner. It is known that the dynamin coat alone, without GTP, can constrict membrane tubes to radii of ∼10 nm, indicating that the intrinsic shape and elasticity of dynamin filaments should play an important role in membrane remodeling.

I'm tired and feel like drinking: Viewing alcohol cues after exerting self-control increases approach motivation among individuals lower in alcohol sensitivity.

Exerting self-control depletes capacity for future self-control, which can promote greater alcohol use. However, certain populations may be more susceptible to these effects of depleted self-control capacity. For example, individuals with lower alcohol sensitivity (i.

Using SMOG 2 to Simulate Complex Biomolecular Assemblies.

Over the last 20 years, the application of structure-based (Gō-like) models has ranged from protein folding with coarse-grained models to all-atom representations of large-scale molecular assemblies. While there are many variants that may be employed, the common feature of these models is that some (or all) of the stabilizing energetic interactions are defined based on the knowledge of a particular experimentally obtained conformation. With the generality of this approach, there was a need for a versatile computational platform for designing and implementing this class of models.

Structure and assembly of the mitochondrial membrane remodelling GTPase Mgm1.

Balanced fusion and fission are key for the proper function and physiology of mitochondria. Remodelling of the mitochondrial inner membrane is mediated by the dynamin-like protein mitochondrial genome maintenance 1 (Mgm1) in fungi or the related protein optic atrophy 1 (OPA1) in animals. Mgm1 is required for the preservation of mitochondrial DNA in yeast, whereas mutations in the OPA1 gene in humans are a common cause of autosomal dominant optic atrophy-a genetic disorder that affects the optic nerve.

Studying ribosome dynamics with simplified models.

With the broad accessibility of high-performance computing resources, the significance of a molecular dynamics simulation is now rarely limited by hardware and/or software availability. Rather, the scientific value of each calculation is determined by the principles that underlie the theoretical model. The current review addresses this topic in the context of simplified models applied to large-scale (∼20-100 Å) dynamics in the ribosome.

Of two minds about alcohol: Specific effects of evaluative conditioning on implicit, but not explicit, alcohol cognitions among heavy versus light drinkers.

Heavy episodic drinking (HED) is a dangerous and pervasive problem in college populations. Two experiments examined the asymmetric effects of evaluative conditioning (EC) on cognitions underlying HED in a nonclinical, student sample. Based on the associative-propositional evaluation (APE) model, we predicted that negative EC would result in stronger implicit alcohol avoidance motivation compared to neutral EC but would not impact explicit alcohol expectancies; further, we hypothesized stronger negative EC effects among students reporting HED compared to light drinkers.

In the eye of the drinker: Drinking motives influence the effectiveness of conditioning implicit alcohol attitudes.

Risky alcohol use is prevalent among college students. Pre-intervention research has established methods of influencing alcohol cognition and reducing short-term alcohol consumption among students using evaluative conditioning (EC), repeatedly pairing alcohol with emotionally valenced images. Specifically, negative EC promotes negative attitudes toward alcohol, but additional research is needed to understand the range of EC effects and conditions under which it is or is not effective.

Structural basis for membrane tethering by a bacterial dynamin-like pair.

Dynamin-like proteins (DLPs) are large GTPases that restructure membrane. DLPs such as the mitofusins form heterotypic oligomers between isoform pairs that bridge and fuse opposing membranes. In bacteria, heterotypic oligomerisation may also be important for membrane remodelling as most DLP genes are paired within operons.

Atomistic simulations indicate the functional loop-to-coiled-coil transition in influenza hemagglutinin is not downhill.

Influenza hemagglutinin (HA) mediates viral entry into host cells through a large-scale conformational rearrangement at low pH that leads to fusion of the viral and endosomal membranes. Crystallographic and biochemical data suggest that a loop-to-coiled-coil transition of the B-loop region of HA is important for driving this structural rearrangement. However, the microscopic picture for this proposed "spring-loaded" movement is missing.

Molecular Simulations Suggest a Force-Dependent Mechanism of Vinculin Activation.

Focal adhesions are dynamic constructs at the leading edge of migrating cells, linking them to the extracellular matrix and enabling force sensing and transmission. The lifecycle of a focal adhesion is a highly coordinated process involving spatial and temporal variations of protein composition, interaction, and cellular tension. The assembly of focal adhesions requires the recruitment and activation of vinculin.

Anisotropic Fluctuations in the Ribosome Determine tRNA Kinetics.

The ribosome is a large ribonucleoprotein complex that is responsible for the production of proteins in all organisms. Accommodation is the process by which an incoming aminoacyl-tRNA (aa-tRNA) molecule binds the ribosomal A site, and its kinetics has been implicated in the accuracy of tRNA selection. In addition to rearrangements in the aa-tRNA molecule, the L11 stalk can undergo large-scale anisotropic motions during translation.

Lowered pH Leads to Fusion Peptide Release and a Highly Dynamic Intermediate of Influenza Hemagglutinin.

Hemagglutinin (HA), the membrane-bound fusion protein of the influenza virus, enables the entry of virus into host cells via a structural rearrangement. There is strong evidence that the primary trigger for this rearrangement is the low pH environment of a late endosome. To understand the structural basis and the dynamic consequences of the pH trigger, we employed explicit-solvent molecular dynamics simulations to investigate the initial stages of the HA transition.

SMOG 2: A Versatile Software Package for Generating Structure-Based Models.

Molecular dynamics simulations with coarse-grained or simplified Hamiltonians have proven to be an effective means of capturing the functionally important long-time and large-length scale motions of proteins and RNAs. Originally developed in the context of protein folding, structure-based models (SBMs) have since been extended to probe a diverse range of biomolecular processes, spanning from protein and RNA folding to functional transitions in molecular machines. The hallmark feature of a structure-based model is that part, or all, of the potential energy function is defined by a known structure.