The unbinding dynamics of complexes involving cell-adhesion molecules depends on the specific ligands. Atomic force microscopy measurements have shown that for P-selectin–P-selectin glycoprotein ligand (sPSGL-1) average bond lifetime 〈 t 〉 initially increases (catch bonds) at low (≤10 pN) constant force, f , and decreases when > 10 pN (slip bonds). In contrast, complex with G1 anti-P-selectin monoclonal antibody monotonically . To quantitatively map energy landscape such we use a model...

We characterized the α-to-β transition in α-helical coiled-coil connectors of human fibrin(ogen) molecule using biomolecular simulations their forced elongation and theoretical modeling. The force (F)-extension (X) profiles show three distinct regimes: (1) elastic regime, which coiled coils act as entropic springs (F < 100-125 pN; X 7-8 nm); (2) constant-force plastic by a force-plateau ≈ 150 10-35 (3) nonlinear regime > 175-200 40-50 nm). In three-stranded α-helices undergo noncooperative...

Prokaryotes mostly lack membranous compartments that are typical of eukaryotic cells, but instead, they have various protein-based organelles. These include bacterial microcompartments like the carboxysome and virus-like nanocompartment encapsulin. Encapsulins an adaptable mechanism for enzyme packaging, which makes it attractive platform to carry a foreign protein cargo. Here we investigate assembly pathways mechanical properties cargo-free cargo-loaded nanocompartments, using combination...

Microtubules, the primary components of chromosome segregation machinery, are stabilized by longitudinal and lateral non-covalent bonds between tubulin subunits. However, thermodynamics these microtubule physico-chemical properties poorly understood. Here, we explore biomechanics polymers using multiscale computational modeling nanoindentations in silico a contiguous fragment. A close match simulated experimental force-deformation spectra enabled us to correlate with dynamic structural...

Elucidating the structure-function relationships for therapeutic RNA mimicking phosphorodiamidate morpholino oligonucleotides (PMOs) is challenging due to lack of information about their structures. While PMOs have been approved by US Food and Drug Administration treatment Duchenne muscular dystrophy, no structural on these unique, charge-neutral, stable molecules available. We performed circular dichroism solution viscosity measurements combined with molecular dynamics simulations machine...

Theoretical exploration of fundamental biological processes involving the forced unraveling multimeric proteins, sliding motion in protein fibers and mechanical deformation biomolecular assemblies under physiological force loads is challenging even for distributed computing systems. Using a C(α)-based coarse-grained self organized polymer (SOP) model, we implemented Langevin simulations proteins on graphics processing units (SOP-GPU program). We assessed computational performance an...

Using a combined experimental and theoretical approach named binding-unbinding correlation spectroscopy (BUCS), we describe the two-dimensional kinetics of interactions between fibrinogen integrin αIIbβ3, ligand-receptor pair essential for platelet function during hemostasis thrombosis. The methodology uses optical trap to probe force-free association individual surface-attached αIIbβ3 molecules forced dissociation an αIIbβ3-fibrinogen complex. This novel combines force clamp measurements...

Accurate chromosome segregation in mitosis depends on proper connections of sister chromatids, through microtubules, to the opposite poles early mitotic spindle. Transiently, many inaccurate are formed and rapidly corrected throughout stages, but a small number merotelic connections, which chromatid is connected both spindle poles, remain lagging at spindle’s equator anaphase. Most chromatids eventually moved one or other pole, likely by combination microtubules’ turnover brute force pulling...

Mechanisms of blood clot contraction – platelet-driven fibrin network remodeling, are not fully understood. We developed a detailed computational ClotDynaMo model with activated platelets, whose rate for normal 450,000/µl human platelets depends on serum viscosity η, platelet filopodia length l, and weakly traction force f extension-retraction speed v. Final volume is independent but v, l. Analysis output revealed 2.24 TJ/mol free energy change, ~67% entropy ~33% internal changes. The...

Fibrin forms a polymeric scaffold of blood clots, which are subjected to deformation in their dynamic environment. The extensible fibrin network allows fibers stretch without breaking, but the mechanisms forced elongation not understood. We combined atomic force microscopy, computer simulations, and Machine Learning explore nanomechanics double-stranded cross-linked oligomers (FO). From experimental force-extension profiles, median 63 pN unfolding 8.1 nm peak-to-peak distance with...

We studied the hydrodynamic behavior of fibrinogen, a blood plasma protein involved in clotting, broad 0.3-60 mg/mL range concentration and 5-42 °C temperature using pulsed-field gradient 1H NMR-diffusometry. Arrhenius plots revealed activation energy for fibrinogen diffusion Ed = 21.3 kJ/mol at 1.4 28.4 38 mg/mL. found dramatic slowdown self-diffusion with beginning 1.7-3.4 mg/mL, which deviated from standard hard-particle behavior, suggesting remarkable intermolecular entanglement. This...

Binding of soluble fibrinogen to the activated conformation integrin αIIbβ3 is required for platelet aggregation and mediated exclusively by C-terminal AGDV-containing dodecapeptide (γC-12) sequence γ chain. However, peptides containing Arg-Gly-Asp (RGD) sequences located in two places Aα chain inhibit binding make substantial contributions when immobilized it converted fibrin. Here, we employed optical trap-based nanomechanical measurements computational molecular modeling determine...

Microtubules are found in most eukaryotic cells, with homologs eubacteria and archea, they have functional roles mitosis, cell motility, intracellular transport, the maintenance of shape. Numerous efforts been expended over last two decades to characterize interactions between microtubules wide variety microtubule associated proteins that control their dynamic behavior cells resulting being assembled disassembled where when required by cell. We present main findings regarding polymerization...

Fibrin formation and mechanical stability are essential in thrombosis hemostasis. To reveal how load impacts fibrin, we carried out optical trap-based single-molecule forced unbinding experiments. The strength of noncovalent A:a knob-hole bond stabilizing fibrin polymers first increases with tensile force (catch bonds) then decreases when the exceeds a critical value (slip bonds). provide structural basis catch-slip-bond behavior, analyzed crystal structures performed molecular modeling...

Stochastic trajectories in single molecule kinetics coupled to several Gaussian Markovian coordinates are analyzed using a generating function obtained by solving the multidimensional Smoluchowski equation. Multitime correlation functions computed and used identify direct signatures of non-Poissonian resulting from coupling slow coordinates. Effects various degrees between collective with multiple time scales studied.

The use of graphics processing units (GPUs) in simulation applications offers a significant speed gain as compared to computations on central (CPUs). Many methods require large number independent random variables generated at each step. We present two approaches for implementation generators (RNGs) GPU. In the one-RNG-per-thread approach, one RNG produces stream numbers thread execution, whereas one-RNG-for-all-threads method builds ability different threads communicate, thus, sharing seeds...

Polymerization of fibrin, the primary structural protein blood clots and thrombi, occurs through binding knobs 'A' 'B' in central nodule fibrin monomer to complementary holes 'a' 'b' beta- gamma-nodules, respectively, another monomer. We characterized A:a B:b knob-hole interactions under varying solution conditions using Molecular Dynamics simulations models fibrin(ogen) fragment D complexed with synthetic peptides GPRP (knob mimetic) GHRP mimetic). The strength complexes was roughly equal,...