اشترك بالحزمة الذهبية واحصل على وصول غير محدود شمرا أكاديميا
تسجيل مستخدم جديدDesign principles governing the motility of myosin V
194
0
0.0
(
0
)
اسأل ChatGPT حول البحث
ﻻ يوجد ملخص باللغة العربية
The molecular motor myosin V exhibits a wide repertoire of pathways during the stepping process, which is intimately connected to its biological function. The best understood of these is hand-over-hand stepping by a swinging lever arm movement toward the plus-end of actin filaments, essential to its role as a cellular transporter. However, single-molecule experiments have also shown that the motor foot stomps, with one hand detaching and rebinding to the same site, and backsteps under sufficient load. Explaining the complete taxonomy of myosin Vs load-dependent stepping pathways, and the extent to which these are constrained by motor structure and mechanochemistry, are still open questions. Starting from a polymer model, we develop an analytical theory to understand the minimal physical properties that govern motor dynamics. In particular, we solve the first-passage problem of the head reaching the target binding site, investigating the competing effects of load pulling back at the motor, strain in the leading head that biases the diffusion in the direction of the target, and the possibility of preferential binding to the forward site due to the recovery stroke. The theory reproduces a variety of experimental data, including the power stroke and slow diffusive search regimes in the mean trajectory of the detached head, and the force dependence of the forward-to-backward step ratio, run length, and velocity. The analytical approach yields a formula for the stall force, identifying the relative contributions of the chemical cycle rates and mechanical features like the bending rigidities of the lever arms. Most importantly, by fully exploring the design space of the motor, we predict that myosin V is a robust motor whose dynamical behavior is not compromised by reasonable perturbations to the reaction cycle, and changes in the architecture of the lever arm.
قيم البحث
اقرأ أيضاً
Cytoskeletons are self-organized networks based on polymerized proteins: actin, tubulin, and driven by motor proteins, such as myosin, kinesin and dynein. Their positive Darwinian evolution enables them to approach optimized functionality (self-organ
ized criticality). The principal features of the eukaryotic evolution of the cytoskeleton motor protein myosin-1 parallel those of actin and tubulin, but also show striking differences connected to its dynamical function. Optimized (long) hydropathic waves characterize the molecular level Darwinian evolution towards optimized functionality (self-organized criticality). The N-terminal and central domains of myosin-1 have evolved in eukaryotes at different rates, with the central domain hydropathic extrema being optimally active in humans. A test shows that hydropathic scaling can yield accuracies of better than 1% near optimized functionality. Evolution towards synchronized level extrema is connected to a special function of Mys-1 in humans involving Golgi complexes.
Intrinsically disordered proteins (IDPs) do not possess well-defined three-dimensional structures in solution under physiological conditions. We develop all-atom, united-atom, and coarse-grained Langevin dynamics simulations for the IDP alpha-synucle
in that include geometric, attractive hydrophobic, and screened electrostatic interactions and are calibrated to the inter-residue separations measured in recent smFRET experiments. We find that alpha-synuclein is disordered with conformational statistics that are intermediate between random walk and collapsed globule behavior. An advantage of calibrated molecular simulations over constraint methods is that physical forces act on all residues, not only on residue pairs that are monitored experimentally, and these simulations can be used to study oligomerization and aggregation of multiple alpha-synuclein proteins that may precede amyloid formation.
We analyze the problem of the helix-coil transition in explicit solvents analytically by using spin-based models incorporating two different mechanisms of solvent action: explicit solvent action through the formation of solvent-polymer hydrogen bonds
that can compete with the intrinsic intra-polymer hydrogen bonded configurations (competing interactions) and implicit solvent action, where the solvent-polymer interactions tune biopolymer configurations by changing the activity of the solvent (non-competing interactions). The overall spin Hamiltonian is comprised of three terms: the background emph{in vacuo} Hamiltonian of the Generalized Model of Polypeptide Chain type and two additive terms that account for the two above mechanisms of solvent action. We show that on this level the solvent degrees of freedom can be {sl explicitly} and {sl exactly} traced over, the ensuing effective partition function combining all the solvent effects in a unified framework. In this way we are able to address helix-coil transitions for polypeptides, proteins, and DNA, with different buffers and different external constraints. Our spin-based effective Hamiltonian is applicable for treatment of such diverse phenomena as cold denaturation, effects of osmotic pressure on the cold and warm denaturation, complicated temperature dependence of the hydrophobic effect as well as providing a conceptual base for understanding the behavior of Intrinsically Disordered Proteins and their analogues.
Solutions of manually purified gastric mucins have been shown to be promising lubricants for biomedical purposes, where they can efficiently reduce friction and wear. However, so far, such mucin solutions have been mostly tested in specific settings,
and variations in the composition of the lubricating fluid have not been systematically explored. We here fill this gap and determine the viscosity, adsorption behavior, and lubricity of porcine gastric mucin solutions on hydrophobic surfaces at different pH levels, mucin and salt concentrations and in the presence of other proteins. We demonstrate that mucin solutions provide excellent lubricity even at very low concentrations of 0.01 % (w/v), over a broad range of pH levels and even at elevated ionic strength. Furthermore, we provide mechanistic insights into mucin lubricity, which help explain how certain variations in physiologically relevant parameters can limit the lubricating potential of mucin solutions. Our results motivate that solutions of manually purified mucin solutions can be powerful biomedical lubricants, e.g. serving as eye drops, mouth sprays or as a personal lubricant for intercourse.
The ongoing effort to detect and characterize physical entanglement in biopolymers has so far established that knots are present in many globular proteins and also abound in viral DNA packaged inside bacteriophages. RNA molecules, on the other hand,
have not yet been systematically screened for the occurrence of physical knots. We have accordingly undertaken the systematic profiling of the ~6,000 RNA structures present in the protein data bank. The search identified no more than three deeply-knotted RNA molecules. These are ribosomal RNAs solved by cryo-em and consist of about 3,000 nucleotides. Compared to the case of proteins and viral DNA, the observed incidence of RNA knots is therefore practically negligible. This suggests that either evolutionary selection, or thermodynamic and kinetic folding mechanisms act towards minimizing the entanglement of RNA to an extent that is unparalleled by other types of biomolecules. The properties of the three observed RNA knotting patterns provide valuable clues for designing RNA sequences capable of self-tying in a twist-knot fold.
سجل دخول لتتمكن من نشر تعليقات
التعليقات
جاري جلب التعليقات
سجل دخول لتتمكن من متابعة معايير البحث التي قمت باختيارها
