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Predicting the kinetics of drug-protein interactions is crucial for understanding drug efficacy, particularly in personalized medicine, where protein mutations can significantly alter drug residence times. This study applies Replica Exchange Transition Interface Sampling (RETIS) and its Partial Path variant (REPPTIS) to investigate the dissociation kinetics of imatinib from Abelson nonreceptor tyrosine kinase (ABL) and mutants relevant to chronic myeloid leukemia therapy. These path-sampling methods offer a bias-free alternative to conventional approaches requiring qualitative predefined reaction coordinates.

Striga hermonthica is a parasitic weed that destroys billions of dollars’ worth of staple crops every year. Its rapid proliferation stems from an enhanced ability to metabolize strigolactones (SLs), plant hormones that direct root branching and shoot growth. Striga’s SL receptor, ShHTL7, bears more similarity to the staple crop karrikin receptor KAI2 than to SL receptor D14, though KAI2 variants in plants like Arabidopsis thaliana show minimal SL sensitivity. Recently, studies have indicated that a small number of point mutations to HTL7 residues can confer SL sensitivity to AtKAI2.

SIGNIFICANCE It has been extremely challenging to quantify the precise relationships between collective processes in biomolecular assemblies. To this end, we used molecular simulations to identify transient interactions that couple two large-scale rearrangements in the ribosome: subunit rotation and tRNA hybrid formation. While subunit rotation in the ribosome is known to be correlated with tRNA movement, these calculations show that their relationship is non-monotonic. That is, while initial rotation accelerates tRNA kinetics, additional rotation leads to a slow down. This provides insights into the precise physicochemical properties of the ribosome, while demonstrating a general strategy that may be used to dissect the dynamics of other complex molecular machines.

The attachment of bacteria to solid surfaces has been studied primarily through the modes of pili or flagella tethering. We report on a common feature of tethering in pililess strains of three species of monotrichous bacteria—(Vibrio alginolyticus, Pseudomonas aeruginosa, and Caulobacter crescentus)—namely, that they may become tethered to the surface by their cell body rather than by their flagellum. These tethered bacteria rotate in alternating directions about a pivot point located under the cell body.

FtsZ, a bacterial tubulin, plays a crucial role in the cytokinesis process. It shares structural similarities with tubulin, as it consists of two domains – N-terminal and C-terminal domains. The protein assembles to form single-stranded protofilaments that exhibit a dynamic phenomenon known as treadmilling where the FtsZ filaments appear to execute a unidirectional movement even though individual monomers constituting the filament do not move. Despite forming protofilaments, an FtsZ molecule requires a conformational switch to form stable contacts with neighboring subunits in a filament.

Autosomal dominant retinitis pigmentosa (ADRP) is a visual disorder which can result from many different mutations of the rhodopsin gene. In most cases the mutation results in a misfolded rhodopsin protein or a protein that does not bind with the retinal chromophore. Some mutations, however, yield rhodopsins which fold properly and bind the retinal chromophore, yet still result in ADRP. Here we investigate the activation mechanism of one such mutation which produces the G51V rhodopsin variant. Human WT and G51V were recombinantly produced and embedded in identical nanodiscs.

Symmetric homo-oligomeric proteins comprising multiple copies of identical subunits are abundant in all domains of life. To fulfill their biological function, these complexes undergo conformational changes, binding events, or post-translational modifications leading to loss of symmetry. Processivity clamp proteins that encircle DNA and play multiple roles in DNA replication and repair are archetypical homo-oligomeric symmetric protein complexes. The symmetrical nature of processivity clamps enables simultaneous interactions with multiple protein binding partners; such interactions result in asymmetric changes that facilitate the transition between clamp loading and DNA replication, and between DNA replication and repair.

When a blood clot occludes cerebral arteries, causing a stroke, a common cause of global death, thrombolytic therapy steps in as a highly effective treatment to restore the blood flow by dissolving the clot. Thrombolytic therapy is the use of plasminogen activators, including tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA), either separately or in combination. In this study, a mathematical model of thrombolysis has been developed for non-uniform fibrin clots, which have varying density levels nearer and farther from the cell surface.

Significance Statement: This review explains how combining two optical techniques—Förster Resonance Energy Transfer (FRET) and Fluorescence Correlation Spectroscopy (FCS)—can help us better understand how biological molecules move and interact over time and space. This approach offers a broader dynamic range and versatility than traditional methods used to study molecular structure and behavior. The review covers the basics of how FRET-FCS works and explores new ways it’s being used in research. It aims to give scientists from various fields a clear overview of the method’s strengths and potential, especially for investigating complex biological systems.

The assembly of integrin adhesion complexes at the inner leaflet of the plasma membrane regulates cell adhesion to the extracellular matrix. The multivalent protein interactions within the complexes and with the cell membrane display characteristics of membrane-associated biomolecular condensates driven by liquid-liquid phase separation. The composition of lipids and the distribution of the cell membrane are crucial for forming integrin adhesion complexes. Here, we report that PIP2 and PIP3in the model membrane synergistically regulate the formation of membrane-induced integrin adhesion condensates, which consist of β1 tails, kindlin, talin, paxillin, and FAK.

Statement of Significance: While single-cell metastasis is well-studied, mechanisms of collective cluster migration are less understood. Significant challenges include the lack of a fundamental physics perspective on collective cluster migration mechanisms and suitable physiologically relevant three-dimensional (3D) in vitro models that can recapitulate collective cluster migration. In this article, we developed a computational model depicting microtumor migration behaviors. Collective cell migration, with varying correlation lengths, exhibits different migratory modes such as directional and radial migration. These modes are predicted by in silico models and confirmed using experimental microtumor models. Machine learning methods were exploited to identify migratory modes. Our computational and experimental models are flexible in various circumstances, offering insights into cancer migration mechanisms.