A non-Markov ratchet model of molecular motors：processive movement of single-headed kinesin KIF1A

A fluctuating ratchet model of non-Markov process is presented to describe the processive movement of molecular motors of single-headed kinesin KIF1A, where the fluctuation perturbation to the local potential is introduced and the detailed ATPase pathway of the motor is included. The theoretical results show good quantitative agreement with the previous experimental ones.

Dynamic Control of Multiple Optical Patterns of Cholesteric Liquid Crystal Microdroplets by Light-Driven Molecular Motors

The key to high-level encryption and anti-counterfeiting techniques is the storage of multiple levels of distinct information that can be individually and precisely addressed by certain stimuli.This continues to be a formidable challenge as the concealed images or codes must be read with fast response and high resolution without cross-talk to the first layer of information.Here,we report a non-fluorescencebased strategy to establish responsive encryption labels taking advantage of solely tuning multiple optical patterns of cholesteric liquid crystal(CLC)microdroplets doped with light-driven molecular motors.The photo-triggered unidirectional rotation of the motor induced not only changes in the helical twist power value but the opposite helical orientation of the superstructure in CLCs as well,resulting in changes in both the structural color and the selective reflection of circularly polar light.The designed labels,which featured highly selective addressability of dual-level distinct information,good reversibility,and viewing angle-independence,were applied to build devices for daily practical use,demonstrating great potential in anti-counterfeiting technology and provide a versatile platform for enhanced data protection and encryption of authentic information.

Collective mechanism of molecular motors and a dynamic mechanical model for sarcomere

A non-equilibrium statistical method is used to study the collective characteristics of myosin II motors in a sarcomere during its contraction. By means of Fokker-Planck equation of molecular motors, we present a dynamic mechanical model for the sarcomere in skeletal muscle. This model has been solved with a numerical algorithm based on experimental chemical transition rates. The influences of ATP concentration and load on probability density, contraction velocity and maximum active force are discussed respectively. It is shown that contraction velocity and maximum isometric active force increase with the increasing ATP concentration and become constant when the ATP concentration reaches equilibrium saturation. Contraction velocity reduces gradually as the load force increases. We also find that active force begins to increase then decrease with the increasing length of sarcomere, and has a maximum value at the optimal length that all myosin motors can attach to actin filament. Our results are in good agreement with the Hill muscle model.

Insight into the chemomechanical coupling mechanism of kinesin molecular motors

Kinesin is a two-headed biological molecular motor that can walk processively on microtubule via consumption of ATP molecules.The central issue for the molecular motor is how the chemical energy released from ATP hydrolysis is converted to the kinetic energy of the mechanical motion,namely the mechanism of chemomechanical coupling.To address the issue,diverse experimental methods have been employed and a lot of models have been proposed.This review focuses on the proposed models as well as the qualitative and quantitative comparisons between the results derived from the models and those from the structural,biochemical and single-molecule experimental studies.

Coordinated motion of molecular motors on DNA chains with branch topology

To understand the macroscopic mechanical behaviors of responsive DNA hydrogels integrated with DNA motors,we constructed a state map for the translocation process of a single FtsKc on a single DNA chain at the molecular level and then investigated the movement of single or multiple FtsKc motors on DNA chains with varied branch topologies.Our studies indicate that multiple.FtsKc motors can have coordinated motion,which is mainly due to the force-responsive behavior of individual FtsKc motors.We further suggest the potential application of motors of FtsKc,together with DNA chains of specific branch topology,to serve as strain sensors in hydrogels.

Coordinated motion of molecular motors on DNA chains with branch topology

Toward understanding the macroscopic mechanical behaviors of responsive deoxyribonucleic acid(DNA)hydrogels integrated with DNA motors,here we construct the state map for the translocation process of a single C-terminal translocase domain(FtsKC)on a single DNA chain at the molecular level and then investigate the movement of single or multiple FtsKC motors on DNA chains with varied branch topology.Our studies indicate that multiple FtsKC motors can have coordinated motion,which is mainly due to the force responsive behavior of individual FtsKC motor.We further suggest the potential application of motors of FtsKC,together with DNA chains of specific branch topology,to serve as strain sensors in hydrogels.

Translating the action of molecular motors to supramolecular polymers

The amplification of asymmetry from the molecular level to the macroscopic scale is an intriguing mechanism operative in natural systems to control complex functions.Inspired by nature,strategies for transferring chiral information across length scales in purely synthetic systems have been investigated.[1,2]Thereof,chiral molecules are embedded into well-defined ordered supramolecular structures with the dynamics of noncovalent interactions leading to the amplification effect.

Engineering The Neck Hinge Reshapes The Processive Movement of Kinesin-3

Objective In kinesin-3,the neck coil correlates with the following segments to form an extended neck that contains a characteristic hinge diverse from a proline in KIF13B to a long flexible linker in KIF1A.The function of this neck hinge for controlling processive movement,however,remains unclear.Methods We made a series of modifications to the neck hinges of KIF13B and KIF1A and tested their movement using a single-molecule motility assay.Results In KIF13B,the insertion of flexible residues before or after the proline differentially impacts the processivity or velocity,while the removal of this proline increases the both.In KIF1A,the deletion of entire flexible neck hinge merely enhances the processivity.The engineering of these hinge-truncated necks of kinesin-3 into kinesin-1 similarly boosts the processive movement of kinesin-1.Conclusion The neck hinge in kinesin-3 controls its processive movement and proper modifications tune the motor motility,which provides a novel strategy to reshape the processive movement of kinesin motors.

Drug Transport Microdevice Mimicking an Idealized Nanoscale Bio-molecular Motor

Molecular motors are nature＇s nano-devices and the essential agents of movement that are an integral part of many living organisms. The supramolecular motor, called Nuclear Pore Complex （NPC）, controls the transport of all cellular material be- tween the cytoplasm and the nucleus that occurs naturally in biological cells of many organisms. In order to understand the design characteristics of the NPC, we developed a microdevice for drug/fluidic transport mimicking the coarse-grained repre- sentation of the NPC geometry through computational fluid dynamic analysis and optimization. Specifically, the role of the central plug in active fluidic/particle transport and passive transport （without central plug） was investigated. Results of flow rate, pressure and velocity profiles obtained from the models indicate that the central plug plays a major role in transport through this biomolecular machine. The results ofthis investigation show that fluidic transport and flow passages are important factors in designing NPC based nano- and micro-devices for drug delivery.

A simplified tether model for molecular motor transporting cargo

Molecular motors are proteins or protein complexes which function as transporting engines in biological cells. This paper models the tether between motor and its cargo as a symmetric linear potential. Different from Elston and Peskin＇s work for which performance of the system was discussed only in some limiting cases, this study produces analytic solutions of the problem for general cases by simplifying the transport system into two physical states, which makes it possible to discuss the dynamics of the motor--cargo system in detail. It turns out that the tether strength between motor and cargo should be greater than a threshold or the motor will fail to transport the cargo, which was not discussed by former researchers yet. Value of the threshold depends on the diffusion coefficients of cargo and motor and also on the strength of the Brownian ratchets dragging the system. The threshold approaches a finite constant when the strength of the ratchet tends to infinity.

Periodic thermodynamics of laser-driven molecular motor

Operation of a laser-driven nano-motor inevitably generates a non-trivial amount of heat, which can possibly lead to instability or even hinder the motor＇s continual running. This work quantitatively examines the overheating problem for a recently proposed laser-operated molecular locomotive. We present a single-molecule cooling theory, in which molecular details of the locomotive system are explicitly treated. This theory is able to quantitatively predict cooling efficiency for various candidates of molecular systems for the locomotive, and also suggests concrete strategies for improving the locomotive＇s cooling. It is found that water environment is able to cool the hot locomotive down to room temperature within 100 picoseconds after photon absorption. This cooling time is a few orders of magnitude shorter than the typical time for laser operation, effectively preventing any overheating for the nano-locomotive. However, when the cooling is less effective in non-aqueous environment, residual heat may build up. A continuous running of the motor will then lead to a periodic thermodynamics, which is a common character of many laser-operated nano-devices.

A Theoretical Investigation on Rectifying Performance of a Single Motor Molecular Device

We report ab initio calculations of the transport behavior of a phenyl substituted molecular motor. The calculated results show that the transport behavior of the device is sensitive to the rotation degree of the rotor part. When the rotor part is parallel with the stator part, a better rectifying performance can be found in the current-voltage curve. However, when the rotor part revolves to vertical with the stator part, the currents in the positive bias region decrease slightly. More importantly, the rectifying performance disappears. Thus this offers us a new method to modulate the rectifying behavior in molecular devices.

Inhibition of kinesin-5 improves regeneration of injured axons by a novel microtubule-based mechanism

Microtubules have been identified as a powerful target for augmenting regeneration of injured adult axons in the central nervous system. Drugs that stabilize microtubules have shown some promise, but there are concerns that abnormally stabilizing microtubules may have only limited benefits for regeneration, while at the same time may be detrimental to the normal work that microtubules perform for the axon. Kinesin-5 （also called kifl I or EgS）, a molecular motor protein best known for its crucial role in mitosis, acts as a brake on microtubule movements by other motor proteins in the axon. Drugs that inhibit kinesin-5, originally developed to treat cancer, result in greater mobility of microtubules in the axon and an overall shift in the forces on the microtubule array. As a result, the axon grows faster, retracts less, and more readily enters environments that are inhibitory to axonal regeneration. Thus, drugs that inhibit kinesin-5 offer a novel microtubule-based means to boost axonal regeneration without the concerns that accompany abnormal stabilization of the microtubule array. Even so, inhibiting kinesin-5 is not without its own caveats, such as potential problems with navigation of the regenerating axon to its target, as well as morphological effects on dendrites that could affect learning and memory if the drugs reach the brain.

Modelling of a DNA packaging motor

During the assembly of many viruses, a powerful molecular motor packages the genome into a preassembled capsid. The Bacillus subtilis phage φ29 is an excellent model system to investigate the DNA packaging mechanism because of its highly efficient in vitro DNA packaging activity and the development of a single-molecule packaging assay. Here we make use of structural and biochemical experimental data to build a physical model of DNA packaging by the φ29 DNA packaging motor. Based on the model, various dynamic behaviours such as the packaging rate, pause frequency and slip frequency under different ATP concentrations, ADP concentrations, external loads as well as capsid fillings are studied by using Monte Carlo simulation. Good agreement is obtained between the simulated and available experimental results. Moreover, we make testable predictions that should guide future experiments related to motor function.

Brownian ratchet mechanism of translocation in T7 RNA polymerase facilitated by a post-translocation energy bias arising from the conformational change of the enzyme

T7 RNA polymerase can transcribe DNA to RNA by translocating along the DNA. Structural studies suggest that the pivoting rotation of the O helix in the fingers domain may drive the movement of the O helix C-terminal Tyr639 from pre- to post-translocation positions. In a series of all-atom molecular dynamics simulations, we show that the movement of Tyr639 is not tightly coupled to the rotation of the O helix, and that the two processes are only weakly dependent on each other. We also show that the internal potential of the enzyme itself generates a small difference in free energy （△E） between the post- and pre-translocation positions of Tyr639. The calculated value of △E is consistent with that obtained from single-molecule experimental data. These findings lend support to a model in which the translocation takes place via a Brownian ratchet mechanism, with the small free energy bias △E arising from the conformational change of the enzyme itself.

Artificial molecular machines that can perform work

An artificial molecular machine consists of molecule or substituent components jointed together in a specific way so that their mutual displacements could be initiated using appropriate outside stimuli. Such an ability of performing mechanical motions by consuming external energy has endowed these tiny machines with vast fascinating potential applications in areas such as actuators, manipulating atoms/molecules, drug delivery, molecular electronic devices, etc. To date, although vast kinds of molecular machine archetypes have been synthesized in facile ways, they are inclined to be defined as switches but not true machines in most cases because no useful work has been done during a working cycle. More efforts need to be devoted on the utilization and amplification of the nanoscale mechanical motions among synthetic molecular machines to accomplish useful tasks. Here we highlight some of the recent advances relating to molecular machines that can perform work on different length scales, ranging from microscopic levels to macroscopic ones.

Alternative relay regulates the adenosine triphosphatase activity of Locusta migratoria striated muscle myosin

Locust(Locusta migratoria)has a single striated muscle myosin heavy chain(Mhc)gene,which contains 5 clusters of alternative exclusive exons and 1 differently included penultimate exon.The alternative exons of Mhc gene encode 4 distinct regions in the myosin motor domain,that is,the N-terminal SH3-like domain,one lip of the nucleotide-binding pocket,the relay,and the converter.Here,we investigated the role of the alternative regions on the motor function of locust muscle myosin.Using Sf9-baculovirus protein expression system,we expressed and purified 5 isoforms of the locust muscle myosin heavy meromyosin(HMM),including the major isoform in the thorax dorsal longitudinal flight muscle(FL1)and 4 isoforms expressed in the abdominal intersegmental muscle(AB1 to AB4).Among these 5 HMMs,FL1-HMM displayed the highest level of actin-activated adenosine triphosphatase(ATPase)activity(hereafter referred as ATPase activity).To identify the alternative region(s)responsible for the elevated ATPase activity of FL1-HMM,we produced a number of chimeras of FL1-HMM and AB4-HMM.Substitution with the relay of AB4-HMM(encoded by exon-14c)substantially decreased the ATPase activity of FL1-HMM,and conversely,the relay of FL1-HMM(encoded by exon-14a)enhanced the ATPase activity of AB4-HMM.Mutagenesis showed that the exon-14a-encoded residues Gly474 and Asn509 are responsible for the elevated ATPase activity of FL1-HMM.Those results indicate that the alternative relay encoded by exon-14a/c play a key role in regulating the ATPase activity of FL1-HMM and AB4-HMM.

Effects of rebinding rate and asymmetry in unbinding rate on cargo transport by multiple kinesin motors

Many intracellular transports are performed by multiple molecular motors in a cooperative manner.Here,we use stochastic simulations to study the cooperative transport by multiple kinesin motors,focusing mainly on effects of the form of unbinding rate versus force and the rebinding rate of single motors on the cooperative transport.We consider two forms of the unbinding rate.One is the symmetric form with respect to the force direction,which is obtained according to Kramers theory.The other is the asymmetric form,which is obtained from the prior studies for the single kinesin motor.With the asymmetric form the simulated results of both velocity and run length of the cooperative transport by two identical motors and those by a kinesin-1 motor and a kinesin-2 motor are in quantitative agreement with the available experimental data,whereas with the symmetric form the simulated results are inconsistent with the experimental data.For the cooperative transport by a faster motor and a much slower motor,the asymmetric form can give both larger velocity and longer run length than the symmetric form,giving an explanation for why kinesin adopts the asymmetric form of the unbinding rate rather than the symmetric form.For the cooperative transport by two identical motors,while the velocity is nearly independent of the rebinding rate,the run length increases linearly with the rebinding rate.For the cooperative transport by two different motors,the increase of the rebinding rate of one motor also enhances the run length of the cooperative transport.The dynamics of transport by N(N=3,4,5,6,7 and 8)motors is also studied.

Pharmacologically targeting molecular motor promotes mitochondrial fission for anti-cancer

Mitochondrial shape rapidly changes by dynamic balance of fusion and fission to adjust to constantly changing energy demands of cancer cells.Mitochondrial dynamics balance is exactly regulated by molecular motor consisted of myosin and actin cytoskeleton proteins.Thus,targeting myosin eactin molecular motor is considered as a promising strategy for anti-cancer.In this study,we performed a proof-of-concept study with a natural-derived small-molecule J13 to test the feasibility of anti-cancer therapeutics via pharmacologically targeting molecular motor.Here,we found J13 could directly target myosin-9(MYH9)eactin molecular motor to promote mitochondrial fission progression,and markedly inhibited cancer cells survival,proliferation and migration.Mechanism study revealed that J13 impaired MYH9 eactin interaction to inactivate molecular motor,and caused a cytoskeleton-dependent mitochondrial dynamics imbalance.Moreover,stable isotope labeling with amino acids in cell culture(SILAC)technology-coupled with pulldown analysis identified HSPA9 as a crucial adaptor protein connecting MYH9 eactin molecular motor to mitochondrial fission.Taken together,we reported the first natural small-molecule directly targeting MYH9 eactin molecular motor for anti-cancer translational research.Besides,our study also proved the conceptual practicability of pharmacologically disrupting mitochondrial fission/fusion dynamics in human cancer therapy.

Recent advances in new-type molecular switches

Molecular switches that can undergo reversible switching between two or more different states in response to external stimuli have been used in the fabrication of various optoelectronic devices and smart materials for many decades, and also found many applications in sensing, molecular self-assembly and photo-controlled biological systems. Recently, mechanically interlocked molecules, such as rotaxanes and catenanes, and molecular rotary motors based on overcrowded alkenes have emerged as two new kinds of molecular switches. Some novel applications of above-mentioned molecular switches have been discovered. In this mini review, we mainly highlight noticeable achievements over the past decade in this field, and summarize the applications of new types of molecular switches, for instance, controlling the chiral space to regulate catalytic reaction as organocatalysts, controlling molecular motions, synthesizing a peptide in a sequence-specific manner and modulating the wettability of the self-assembled monolayers.