scholarly journals On the Importance of Hydrodynamic Interactions in the Stepping Kinetics of Kinesin

2016 ◽  
Author(s):  
Dave Thirumalai ◽  
Yonathan Goldtzvik ◽  
Zhechun Zhang
Keyword(s):  
Coiled Coil ◽  
Quantitative Agreement ◽  
Single Step ◽  
Hydrodynamic Interactions ◽  
Coarse Grained ◽  
Coarse Grained Model ◽  
Target Binding ◽  
Conventional Kinesin ◽  
Kinetics Of ◽  
Target Binding Site

Conventional kinesin walks by a hand-over-hand mechanism on the microtubule (MT) by taking ∼ 8nmdiscrete steps, and consumes one ATP molecule per step. The time needed to complete a single step is on the order of twenty microseconds. We show, using simulations of a coarse-grained model of the complex containing the two motor heads, the MT, and the coiled coil that in order to obtain quantitative agreement with experiments for the stepping kinetics hydrodynamic interactions (HI) have to be included. In simulations without hydrodynamic interactions spanning nearly twenty microseconds not a single step was completed in hundred trajectories. In sharp contrast, nearly 14% of the steps reached the target binding site within 6 microseconds when HI were included. Somewhat surprisingly, there are qualitative differences in the diffusion pathways in simulations with and without HI. The extent of movement of the trailing head of kinesin on the MT during the diffusion stage of stepping is considerably greater in simulations with HI than in those without HI. Our results suggest that inclusion of HI is crucial in the accurate description of motility of other motors as well.

scholarly journals Parsing the roles of neck-linker docking and tethered head diffusion in the stepping dynamics of kinesin

2017 ◽  
Vol 114 (46) ◽  
pp. E9838-E9845 ◽  
Author(s):  
Zhechun Zhang ◽  
Yonathan Goldtzvik ◽  
D. Thirumalai
Keyword(s):  
Single Step ◽  
Coarse Grained ◽  
Power Stroke ◽  
Stochastic Motion ◽  
Coarse Grained Model ◽  
Correct Orientation ◽  
Stall Force ◽  
Target Binding ◽  
The Individual ◽  
Motor Head

Kinesin walks processively on microtubules (MTs) in an asymmetric hand-over-hand manner consuming one ATP molecule per 16-nm step. The individual contributions due to docking of the approximately 13-residue neck linker to the leading head (deemed to be the power stroke) and diffusion of the trailing head (TH) that contributes in propelling the motor by 16 nm have not been quantified. We use molecular simulations by creating a coarse-grained model of the MT–kinesin complex, which reproduces the measured stall force as well as the force required to dislodge the motor head from the MT, to show that nearly three-quarters of the step occurs by bidirectional stochastic motion of the TH. However, docking of the neck linker to the leading head constrains the extent of diffusion and minimizes the probability that kinesin takes side steps, implying that both the events are necessary in the motility of kinesin and for the maintenance of processivity. Surprisingly, we find that during a single step, the TH stochastically hops multiple times between the geometrically accessible neighboring sites on the MT before forming a stable interaction with the target binding site with correct orientation between the motor head and the α/β tubulin dimer.

Retardation of the reaction kinetics of polymers due to entanglement in the post-gel stage in multi-chain slip-spring simulations

Soft Matter ◽  
2019 ◽  
Vol 15 (25) ◽  
pp. 5109-5115 ◽  
Author(s):  
Yuichi Masubuchi ◽  
Takashi Uneyama
Keyword(s):  
Reaction Kinetics ◽  
Reaction Rate ◽  
Network Formation ◽  
Coarse Grained ◽  
Coarse Grained Model ◽  
Kinetics Of ◽  
Standing Problem ◽  
Apparent Reaction Rate

The retardation in the apparent reaction rate in the network formation of polymers is a long-standing problem. We have tackled this issue by a coarse-grained model to clarify the effect of entanglement between polymers.

scholarly journals Kinematics of the lever arm swing in myosin VI

2017 ◽  
Vol 114 (22) ◽  
pp. E4389-E4398 ◽  
Author(s):  
Mauro L. Mugnai ◽  
D. Thirumalai
Keyword(s):  
Rotational Diffusion ◽  
Quantitative Agreement ◽  
Motor Domain ◽  
Coarse Grained ◽  
Power Stroke ◽  
Myosin Vi ◽  
Step Size ◽  
Arm Swing ◽  
Coarse Grained Model ◽  
Lever Arm

Myosin VI (MVI) is the only known member of the myosin superfamily that, upon dimerization, walks processively toward the pointed end of the actin filament. The leading head of the dimer directs the trailing head forward with a power stroke, a conformational change of the motor domain exaggerated by the lever arm. Using a unique coarse-grained model for the power stroke of a single MVI, we provide the molecular basis for its motility. We show that the power stroke occurs in two major steps. First, the motor domain attains the poststroke conformation without directing the lever arm forward; and second, the lever arm reaches the poststroke orientation by undergoing a rotational diffusion. From the analysis of the trajectories, we discover that the potential that directs the rotating lever arm toward the poststroke conformation is almost flat, implying that the lever arm rotation is mostly uncoupled from the motor domain. Because a backward load comparable to the largest interhead tension in a MVI dimer prevents the rotation of the lever arm, our model suggests that the leading-head lever arm of a MVI dimer is uncoupled, in accord with the inference drawn from polarized total internal reflection fluorescence (polTIRF) experiments. Without any adjustable parameter, our simulations lead to quantitative agreement with polTIRF experiments, which validates the structural insights. Finally, in addition to making testable predictions, we also discuss the implications of our model in explaining the broad step-size distribution of the MVI stepping pattern.

scholarly journals Accurate sequence-dependent coarse-grained model for conformational and elastic properties of double-stranded DNA

2021 ◽  
Author(s):  
Salvatore Assenza ◽  
Rubén Pérez
Keyword(s):  
Persistence Length ◽  
Independent Set ◽  
Single Step ◽  
Coarse Grained ◽  
Atomistic Simulations ◽  
Sequence Dependence ◽  
Cellular Processes ◽  
Coarse Grained Model ◽  
Double Stranded Dna ◽  
Sequence Dependent

AbstractWe introduce MADna, a sequence-dependent coarse-grained model of double-stranded DNA (dsDNA), where each nucleotide is described by three beads localized at the sugar and base moieties, and at the phosphate group. The sequence dependence is included by considering a step-dependent parameterization of the bonded interactions, which are tuned in order to reproduce the values of key observables obtained from exhaustive atomistic simulations from literature. The predictions of the model are benchmarked against an independent set of all-atom simulations, showing that it captures with high fidelity the sequence dependence of conformational and elastic features beyond the single step considered in its formulation. A remarkably good agreement with experiments is found for both sequence-averaged and sequence-dependent conformational and elastic features, including the stretching and torsion moduli, the twist-stretch and twist-bend couplings, the persistence length and the helical pitch. Overall, for the inspected quantities, the model has a precision comparable to atomistic simulations, hence providing a reliable coarse-grained description for the rationalization of singlemolecule experiments and the study of cellular processes involving dsDNA. Owing to the simplicity of its formulation, MADna can be straightforwardly included in common simulation engines.

scholarly journals Collapse Precedes Folding in Denaturant-Dependent Assembly of Ubiquitin

2016 ◽  
Author(s):  
Govardhan Reddy ◽  
D. Thirumalai
Keyword(s):  
Single Molecule ◽  
Quantitative Agreement ◽  
Coarse Grained ◽  
Radius Of Gyration ◽  
Structural Elements ◽  
Neutral Ph ◽  
X Ray Scattering ◽  
Unfolded State ◽  
Polypeptide Chains ◽  
Kinetics Of

AbstractDespite the small size the folding of Ubiquitin (Ub), which plays an indispensable role in targeting proteins for degradation and DNA damage response, is complex. A number of experiments on Ub folding have reached differing conclusions regarding the relation between collapse and folding, and whether intermediates are populated. In order to resolve these vexing issues, we elucidate the denaturant-dependent thermodynamics and kinetics of Ub folding in low and neutral pH as a function of Guanidinium chloride and Urea using coarse-grained molecular simulations. The changes in the fraction of the folded Ub, and the radius of gyration (Rg) as a function of the denaturant concentration, [C], are in quantitative agreement with experiments. Under conditions used in experiments,Rgof the unfolded state at neutral pH changes only by ≈ 17% as the [GdmCl] decreases from 6 M to 0 M. We predict that the extent of compaction of the unfolded state increases as temperature decreases. A two-dimensional folding landscape as a function ofRgand a measure of similarity to the folded state reveals unambiguously that the native state assembly is preceded by collapse, as discovered in fast mixing experiments on several proteins. Analyses of the folding trajectories, under mildly denaturing conditions ([GdmCl]=1.0M or [Urea]=1.0M), shows that Ub folds by collision between preformed secondary structural elements involving kinetic intermediates that are primarily stabilized by long-range contacts. Our work explains the results of Small Angle X-Ray Scattering (SAXS) experiments on Ub quantitatively, and establishes that evolved globular proteins are poised to collapse. In the process, we explain the discrepancy between SAXS and single molecule fluorescent resonant energy transfer (smFRET) experiments, which have arrived at a contradicting conclusion concerning the collapse of polypeptide chains.

scholarly journals Unfolding of the chromatin fiber driven by overexpression of bridging factors

2020 ◽  
Author(s):  
Isha Malhotra ◽  
Bernardo Oyarzún ◽  
Bortolo Matteo Mognetti
Keyword(s):  
Microphase Separation ◽  
Single Step ◽  
Chromatin Fiber ◽  
Coarse Grained ◽  
Morphological Properties ◽  
Cross Link ◽  
Simulation Methodology ◽  
Coarse Grained Model ◽  
Nuclear Molecules ◽  
The One

AbstractNuclear molecules control the functional properties of the chromatin fiber by shaping its morphological properties. The biophysical mechanisms controlling how bridging molecules compactify the chromatin are a matter of debate. On the one side, bridging molecules could cross-link faraway sites and fold the fiber through the formation of loops. Interacting bridging molecules could also mediate long-range attractions by first tagging different locations of the fiber and then undergoing microphase separation. Using a coarse-grained model and Monte Carlo simulations, we study the conditions leading to compact configurations both for interacting and non-interacting bridging molecules. In the second case, we report on an unfolding transition at high densities of the bridging molecules. We clarify how this transition, which disappears for interacting bridging molecules, is universal and controlled by entropic terms. In general, chains are more compact in the case of interacting bridging molecules since, in this case, interactions are not valence-limited. However, this result is conditional on the ability of our simulation methodology to relax the system towards its ground state. In particular, we clarify how, unless using reaction dynamics that change the length of a loop in a single step, the system is prone to remain trapped in metastable, compact configurations featuring long loops.

scholarly journals Coarse-Grained Modeling and Molecular Dynamics Simulations of Ca2+-Calmodulin

2021 ◽  
Vol 8 ◽  
Author(s):  
Jules Nde ◽  
Pengzhi Zhang ◽  
Jacob C. Ezerski ◽  
Wei Lu ◽  
Kaitlin Knapp ◽  
...  
Keyword(s):  
Force Field ◽  
Calcium Binding ◽  
Structural Changes ◽  
Tight Binding ◽  
Coarse Grained ◽  
Reciprocal Relation ◽  
Dependent Manner ◽  
Coarse Grained Model ◽  
Target Binding ◽  
Dynamics Simulations

Calmodulin (CaM) is a calcium-binding protein that transduces signals to downstream proteins through target binding upon calcium binding in a time-dependent manner. Understanding the target binding process that tunes CaM’s affinity for the calcium ions (Ca2+), or vice versa, may provide insight into how Ca2+-CaM selects its target binding proteins. However, modeling of Ca2+-CaM in molecular simulations is challenging because of the gross structural changes in its central linker regions while the two lobes are relatively rigid due to tight binding of the Ca2+ to the calcium-binding loops where the loop forms a pentagonal bipyramidal coordination geometry with Ca2+. This feature that underlies the reciprocal relation between Ca2+ binding and target binding of CaM, however, has yet to be considered in the structural modeling. Here, we presented a coarse-grained model based on the Associative memory, Water mediated, Structure, and Energy Model (AWSEM) protein force field, to investigate the salient features of CaM. Particularly, we optimized the force field of CaM and that of Ca2+ ions by using its coordination chemistry in the calcium-binding loops to match with experimental observations. We presented a “community model” of CaM that is capable of sampling various conformations of CaM, incorporating various calcium-binding states, and carrying the memory of binding with various targets, which sets the foundation of the reciprocal relation of target binding and Ca2+ binding in future studies.

scholarly journals Compression stiffening of fibrous networks with stiff inclusions

2020 ◽  
Vol 117 (35) ◽  
pp. 21037-21044
Author(s):  
Jordan L. Shivers ◽  
Jingchen Feng ◽  
Anne S. G. van Oosten ◽  
Herbert Levine ◽  
Paul A. Janmey ◽  
...  
Keyword(s):  
Phase Diagram ◽  
Qualitative Agreement ◽  
Three Dimensional ◽  
Quantitative Agreement ◽  
Coarse Grained ◽  
Fiber Network ◽  
Coarse Grained Model ◽  
Fibrous Network ◽  
Stress Propagation ◽  
Stiffening Effect

Tissues commonly consist of cells embedded within a fibrous biopolymer network. Whereas cell-free reconstituted biopolymer networks typically soften under applied uniaxial compression, various tissues, including liver, brain, and fat, have been observed to instead stiffen when compressed. The mechanism for this compression-stiffening effect is not yet clear. Here, we demonstrate that when a material composed of stiff inclusions embedded in a fibrous network is compressed, heterogeneous rearrangement of the inclusions can induce tension within the interstitial network, leading to a macroscopic crossover from an initial bending-dominated softening regime to a stretching-dominated stiffening regime, which occurs before and independently of jamming of the inclusions. Using a coarse-grained particle-network model, we first establish a phase diagram for compression-driven, stretching-dominated stress propagation and jamming in uniaxially compressed two- and three-dimensional systems. Then, we demonstrate that a more detailed computational model of stiff inclusions in a subisostatic semiflexible fiber network exhibits quantitative agreement with the predictions of our coarse-grained model as well as qualitative agreement with experiments.

scholarly journals Effects of Gold Nanoparticles on the Stepping Trajectories of Kinesin

2020 ◽  
Author(s):  
Sabeeha Hasnain ◽  
Mauro Lorenzo Mugnai ◽  
Dave Thirumalai
Keyword(s):  
Gold Nanoparticles ◽  
Gold Nanoparticle ◽  
Coiled Coil ◽  
Time Dependent ◽  
Coarse Grained ◽  
Dependent Position ◽  
Coarse Grained Simulations ◽  
Conventional Kinesin ◽  
The Right ◽  
Residue Position

Substantial increase in the temporal resolution of the stepping of dimeric molec- ular motors is possible by tracking the position of a large gold nanoparticle (GNP) attached to a labeled site on one of the heads. This technique was used to measure the stepping trajectories of conventional kinesin (Kin1) using the time dependent position of the GNP as a proxy. The trajectories revealed that the detached head always passes to the right of the head that is tightly bound to the microtubule (MT) during a step. In interpreting the results of such experiments, it is implicitly assumed that the GNP does not significantly alter the diffusive motion of the detached head. We used coarse-grained simulations of a system consisting of the MT-Kin1 complex with and without attached GNP to investigate how the stepping trajectories are affected. The two significant findings are: (1) The GNP does not faithfully track the position of the stepping head. (2) The rightward bias is typically exaggerated by the GNP. Both these findings depend on the precise residue position to which the GNP is attached. Surprisingly, we predict that the stepping trajectories of kinesin are not significantly affected if, in addition to the GNP, a 1 μm diameter cargo is attached to the coiled coil. Our simulations suggest the effects of the large probe have to be considered when inferring the stepping mechanisms using GNP tracking experiments.

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