The Kinesin Motor Machine.

How Tiny Cell Proteins Generate Force To 'Walk'

Quote:

ScienceDaily (Dec. 4, 2008) — MIT researchers have shown how a cell motor protein exerts the force to move, enabling functions such as cell division.

Quote:

Kinesin, a motor protein that also carries neurotransmitters, "walks" along cellular beams known as microtubules. For the first time, the MIT team has shown at a molecular level how kinesin generates the force needed to step along the microtubules.

Microtubules, quantum physics, and consciousness? Microtubules form tracks for neurotransmitters to be transported and can possibly act as quantum computational structures.

Quote:

The researchers, led by Matthew Lang, associate professor of biological and mechanical engineering, report their findings in the Nov. 24 online early issue of the Proceedings of the National Academy of Sciences. Because kinesin is involved in organizing the machinery of cell division, understanding how it works could one day be useful in developing therapies for diseases involving out-of-control cell division, such as cancer. The protein consists of two "heads," which walk along the microtubule, and a long "tail," which carries cargo. The heads take turns stepping along the microtubule, at a rate of up to 100 steps (800 nanometers) per second. In the PNAS paper, Lang and his colleagues offer experimental evidence for a model they reported in January in the journal Structure. Their model suggests — and the new experiments confirm — that a small region of the protein, part of which joins the head and tail is responsible for generating the force needed to make kinesin walk. Two protein subunits, known as the N-terminal cover strand and neck linker, line up next to each other to form a sheet, forming the cover-neck bundle that drives the kinesin head forward. "This is the kinesin power stroke," said Lang. Next, Lang's team plans to investigate how the two kinesin heads communicate with each other to coordinate their steps. Lead author of the PNAS paper is Ahmad Khalil, graduate student in mechanical engineering. Other MIT authors of the paper are David Appleyard, a graduate student in biological engineering; Anna Labno, a recent MIT graduate; Adrien Georges, a visiting student in Lang's lab; and Angela Belcher, the Germehausen Professor of Materials Science and Engineering and Biological Engineering. This work is a close collaboration with authors Martin Karplus of Harvard and Wonmuk Hwang of Texas A&M. The research was funded by the National Institutes of Health and the Army Research Office Institute of Collaborative Biotechnologies.

Few videos describing the motor:
Kinesin Transport Protein
Kinesin Explanation

Mice with a few kinesin mutations? Look like there is something wrong with their neurphysiology, almost like they are not interacting with the environment in the correct way?
Kinesin mutations in mice

Ever wondered how cellular machinery causes replication of cells?
Awesome video:
Inside the cell
And it does not even remotely cover the intricate mechanisms controllong the process.

Another video of mitosis:
Mitosis
Active cyclinB/cdc2 plays a part in nuclear envelope breakdown, and destruction of cyclinB and abolition of cdc2 activity allows nuclear envelope formation.

In real life it looks something like this:

Biomolecular machines utilizing thermal fluctuations

Article related to the unique operations of biological molecular machines
Fluctuation as a tool of biological molecular machines
Abstract:

Quote:

The mechanism for biological molecular machines is different from that of man-made ones. Recently single molecule measurements and other experiments have revealed unique operations where biological molecular machines exploit thermal fluctuation in response to small inputs of energy or signals to achieve their function. Understanding and applying this mechanism to engineering offers new artificial machine designs.

The article continues:

Quote:

Biological machines are different from man-made artificial ones in many ways. One primary difference is the amount of energy supplied. For example, a supercomputer playing chess with a champion uses much larger amounts of energy than its adversary. A computer unit element, or IC chip, uses energy much larger than thermal energy (500 times greater) to avoid the disturbance caused from thermal noises whereas biological machines use the energy released from the hydrolysis of ATP, which is only approximately 10 times greater than thermal energy. Large excess energy inputs in computers result in far less efficiency at converting their energy inputs although they are more precise at their task than biological machines. Computers err once per 1060 trials, while basic biochemical reactions underlying biological machines err as often as once per 103 trials. For this reason, computers are in some respects superior to one of nature’s greatest machines, the human brain. Computers make calculations much faster as IC chips work on the order of nanoseconds (10−9 s), while the time scale for basic biochemical reactions in biological machines is milliseconds (10−3 s). They also have superior memory capacity and data transfer rate. The computer rate is on the order of 109 bites/s while in brain it is estimated to be only 400 bites/s. However, biological machines are more flexible, readily responding to changes in their environment. In contrast, man-made machines are designed to maintain their. function regardless of environmental changes. Therefore, the fundamental mechanisms between the two machines are different. Biomolecules and their assemblies, biomolecular machines, are in the order of nanometer in size meaning the effects of thermal noises are large. Nevertheless, biomolecules and molecular machines execute their roles despite these noises. But how? Recent experimental data suggest that biological molecular machines harness thermal fluctuation to achieve their functions. Thus, thermal fluctuation seems to play an important role from the molecular level to cellular and organism level. We have developed measurement systems that trace these thermal fluctuations in biomolecular machines when eliminating measurement noise. Our model biomolecular machine of choice is the molecular motor. Molecular motors are composed of a motor protein, which move using the chemical energy of ATP, and protein tracks, which the motors move along. Molecular motors and protein tracks share unique characteristic properties such as enzymatic activity, molecular recognition, energy conversion and self-organization with other typical molecular machines. Thus the results obtained for molecular motors may be extended to other systems.

Quote:

Thermal fluctuation is involved in function at different hierarchies of biological systems (Fig. 3). In the mechanism for molecular motor motility, it has been shown that thermal fluctuation is involved and biased to generate directional movement. In live cells, a mechanism that utilizes thermal fluctuation is also likely.

Quote:

Lastly, in addition to the stochastic nature at the molecular and cellular levels, visual perception has shown stochastic dynamics. Visual perception processes are explained by equations similar to formulae that govern the behavior of biomolecules (Murata et al., 2003). Thus the mechanisms obtained at molecular and cellular levels likely apply at even higher levels. These mechanisms offer blueprints to engineer artificial machines that utilize fluctuations.

Again, showing the carbon based nanotechnology in cells can be utilized and adopted by our engineers for our own designs seeing that these machines are able to harness even thermal fluctuations.

Paley’s Watch?

Cyanobacteria are one of the organisms with the deepest history, with evidence of their remains dating back possibly to about 3.5 billion years ago. So, what is found in some of these simple cells? CLOCKWORK...

A cyanobacterial circadian clockwork.

Quote:

Cyanobacteria have become a major model system for analyzing circadian rhythms. The temporal program in this organism enhances fitness in rhythmic environments and is truly global--essentially all genes are regulated by the circadian system. The topology of the chromosome also oscillates and possibly regulates the rhythm of gene expression. The underlying circadian mechanism appears to consist of both a post-translational oscillator (PTO) and a transcriptional/translational feedback loop (TTFL). The PTO can be reconstituted in vitro with three purified proteins (KaiA, KaiB, and KaiC) and ATP. These three core oscillator proteins have been crystallized and structurally determined, the only full-length circadian proteins to be so characterized. The timing of cell division is gated by a circadian checkpoint, but the circadian pacemaker is not influenced by the status of the cell division cycle. This imperturbability may be due to the presence of the PTO that persists under conditions in which metabolism is repressed. Recent biochemical, biophysical, and structural discoveries have brought the cyanobacterial circadian system to the brink of explaining heretofore unexplainable biochemical characteristics of a circadian oscillator: the long time constant, precision, and temperature compensation.

On the structure of:
Structural Insights into a Circadian Oscillator

Quote:

An endogenous circadian system in cyanobacteria exerts pervasive control over cellular processes, including global gene expression. Indeed, the entire chromosome undergoes daily cycles of topological changes and compaction. The biochemical machinery underlying a circadian oscillator can be reconstituted in vitro with just three cyanobacterial proteins, KaiA, KaiB, and KaiC. These proteins interact to promote conformational changes and phosphorylation events that determine the phase of the in vitro oscillation. The high-resolution structures of these proteins suggest a ratcheting mechanism by which the KaiABC oscillator ticks unidirectionally. This posttranslational oscillator may interact with transcriptional and translational feedback loops to generate the emergent circadian behavior in vivo. The conjunction of structural, biophysical, and biochemical approaches to this system reveals molecular mechanisms of biological timekeeping.

A biological clock with all the cogs and gears. The KaiABC clock is a bona fide dynamically oscillating nanomachine that precess unidirectionally and robustly. Present in one of the most primitive, simple organisms...

Channel hopping nanomachines

Newly discovered mechanics of a molecular machine that transports proteins.

Channel hopping: protein translocation through the SecA–SecY complex

Quote:

Newly synthesized proteins are translocated across the eukaryotic endoplasmic reticulum membrane or the prokaryotic plasma membrane through an evolutionarily conserved protein conducting channel or translocon known as Sec61 in eukaryotes and SecY in prokaryotes. In bacteria, the SecA ATPase is thought to be the motor for translocation through the SecY channel. Two papers by Tom Rapoport and colleagues report the long-awaited structure of the SecA–SecY complex from bacteria. The structure, reveals major conformational changes between both partners and suggests that SecA uses a two-helix finger to push translocating proteins into SecY's cytoplasmic funnel. Crosslinking studies provide further experimental support for this mechanism. In a third paper, Osamu Nureki and colleagues present a crystal structure of SecY bound to an anti-SecY Fab fragment revealing a pre-open state of the channel. Together these three papers provide novel insights into the path taken by a translocating protein. In News and Views, Anastassios Economou takes stock of where this work leaves current knowledge of this 'astonishing cellular nanomachine'

Research articles:
Structure of a complex of the ATPase SecA and the protein-translocation channel
A role for the two-helix finger of the SecA ATPase in protein translocation
Conformational transition of Sec machinery inferred from bacterial SecYE structures

Quote:

Over 30% of proteins are secreted across or integrated into membranes. Their newly synthesized forms contain either cleavable signal sequences or non-cleavable membrane anchor sequences, which direct them to the evolutionarily conserved Sec translocon (SecYEG in prokaryotes and Sec61, comprising alpha-, bold gamma- and bold beta-subunits, in eukaryotes). The translocon then functions as a protein-conducting channel1. These processes of protein localization occur either at or after translation. In bacteria, the SecA ATPase2, 3 drives post-translational translocation. The only high-resolution structure of a translocon available so far is that for SecYEbold beta from the archaeon Methanococcus jannaschii 4, which lacks SecA. Here we present the 3.2-Å-resolution crystal structure of the SecYE translocon from a SecA-containing organism, Thermus thermophilus. The structure, solved as a complex with an anti-SecY Fab fragment, revealed a 'pre-open' state of SecYE, in which several transmembrane helices are shifted, as compared to the previous SecYEbold beta structure4, to create a hydrophobic crack open to the cytoplasm. Fab and SecA bind to a common site at the tip of the cytoplasmic domain of SecY. Molecular dynamics and disulphide mapping analyses suggest that the pre-open state might represent a SecYE conformational transition that is inducible by SecA binding. Moreover, we identified a SecA–SecYE interface that comprises SecA residues originally buried inside the protein, indicating that both the channel and the motor components of the Sec machinery undergo cooperative conformational changes on formation of the functional complex.

Exquisite control of biomolecular processes with the aid of nanomachines all the way down to the simplest organisms .

Protein Motion

Proteins Have Controlled Motions, Researcher Shows

Quote:

Iowa State University researcher Robert Jernigan believes that his research shows proteins have controlled motions.

Quote:

Most biochemists traditionally believe proteins have many random, uncontrolled movements. Research conducted by Jernigan, director of the L.H. Baker Center for Bioinformatics and Biological Statistics together with Guang Song, an assistant professor in computer science and graduate student Lei Yang, over a 10-year period shows that not only are protein motions more restricted, but also that these restricted, controlled motions are part of the function of the proteins. The group's findings were recently published in the journal "Structure" Using as an example a protein from HIV virus, Jernigan conducted his research using a simple model and tested to see how the proteins moved. The large number of reported structures show exactly the motions that are required for their function, and exactly the same motions as computed by Jernigan's model. "This is one experimental case that is indicative, but there are many others," he said. Jernigan believes this research is the first step to better understanding proteins and cell behaviors. "There is the possibility of creating designer drugs with this newly discovered information," he said. "These are models that conform to the point of view that the structures have been designed to exert very strong control of their motions," he said. "Those motions correspond closely to the motions needed for their function." For instance, HIV virus protein structures that Jer****n studied did not move randomly, but actually opened and closed to allow access to other structures. There is a binding site that must open to permit access to the protein and then close again to allow the protein to function, he said. Because the protein structure opens and closes as part of it function, Jernigan believes that the motion is controlled and part of the function of the protein. Jernigan's studies used the HIV virus, but he believes that the results are relevant to many other protein structures.

So much control, all the way down to protein motion.