RESEARCH: MYOSINS
FOLDING PROJECT #12297 PROFILE

This project studies blebbistatin, a drug that affects muscle proteins called myosins. Myosins power muscle movement, and blebbistatin blocks their function. Researchers use computer simulations to see how blebbistatin binds to different forms of myosin and stops it from working properly. Understanding this could lead to new treatments for muscle diseases.

Note: This TLDR is a simplication and may not be 100% accurate.

These projects are attempts to better understand the behavior of a longstanding drug lead, blebbistatin, and its effects on the motor domain of skeletal muscle myosin.

Myosins are ubiquitous and their motor domains are highly conserved, so while drugging them has potential especially in the context of certain muscle related diseases like hypertrophic cardiomyopathy (a relatively prevalent form of genetic heart disease), understanding how a potential drug interacts with myosin isoforms from first principles will help seed development efforts to avoid side effects. Myosin works by cycling through an ATP hydrolysis (ATP--Adenosine Tri-Phosphate--is the energy currency of the cell, and cutting the third phosphate off hydrolitically is how that currency is spent) driven process where it binds actin, undergoes a conformational (a particular arrangement of the atoms in the protien) change, and then releases actin (allowing collections of myosins to work in concert to pull along the length of an actin fiber).

A common mode of action for inhibitors of myosin is that they will get a motor domain stuck in a particular step in the cycle.

Blebbistatin is an inhibitor that binds to a subclass of myosin at a cryptic site and inhibits phosphate release, which is a necessary step in the cycle. To understand how blebbistatin impacts the conformations the protein can access, we've started simulaitons from four different chemical compositions:

• 12296: Blebbistatin only.

  All other binding sites are vacant.

  Experimentally, blebbistatin is believed to not bind this state.

  We hope to see what impact it may have on the ATP/ADP+Phosphate binding site.

• 12297: ADP, Phosphate, and Blebbistatin.

  This is thought to be the mode of action of blebbistatin.

  It causes the Phosphate present in this conformation to be held more tightly, thus preventing the enzyme from cycling.

• 12298: ADP and Blebbistatin.

  This simulation will allow us to ask what is different about the phosphate binding site when Blebbistatin is present, to see if it maintains conformations that would bind phosphate well even when it is no longer present.

• 12299: ADP only.

  To see how the blebbistatin binding site fluctuates when the phosphate is not present.

  Because blebbistatin is supposed to be selective for the states that are compatible with phosphate binding, this will help us elucidate the coupling between the two sites.

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Blebbistatin

A drug that inhibits myosin.

Blebbistatin is a medication used to study muscle function. It blocks the activity of myosin, a protein essential for muscle contraction. By inhibiting myosin, blebbistatin helps researchers understand how muscles work and explore potential treatments for muscle-related diseases.

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Myosin

A motor protein that converts chemical energy into mechanical work.

Myosin is a vital protein found in muscle cells. It acts like a tiny engine, using energy from ATP to pull on filaments called actin. This pulling action allows muscles to contract and generate force for movement. Myosin plays a crucial role in various biological processes, including muscle contraction, cell division, and intracellular transport.

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ATP

Adenosine Triphosphate

ATP stands for adenosine triphosphate. It's the primary energy currency of cells, providing the power needed for countless biological processes, including muscle contraction, nerve impulse transmission, and protein synthesis. ATP is constantly generated and consumed within cells, ensuring a continuous supply of energy for life.

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ADP

Adenosine Diphosphate

ADP is a molecule derived from ATP when one phosphate group is removed. It serves as an intermediate in energy metabolism, playing a crucial role in the process of cellular respiration, where ATP is generated.

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Phosphate

A chemical group consisting of a phosphorus atom bonded to four oxygen atoms.

Phosphate is a negatively charged ion (PO43-) with essential roles in various biological processes. It's a key component of ATP, DNA, and RNA. Phosphate ions also play crucial roles in energy transfer, signal transduction, and bone formation.

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Actin

A globular protein that forms microfilaments in cells.

Actin is a fundamental protein found in all eukaryotic cells. It's responsible for forming microfilaments, which are thin, flexible fibers crucial for cell shape, movement, and division. Actin also plays a vital role in muscle contraction, interacting with myosin to generate force.

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Hypertrophic Cardiomyopathy

A genetic heart disease characterized by thickened heart muscle.

Hypertrophic cardiomyopathy is a genetic disorder that causes the heart muscle to thicken abnormally. This thickening can make it harder for the heart to pump blood effectively, leading to symptoms like shortness of breath, chest pain, and fatigue. It's often inherited and affects individuals of all ages.