RESEARCH: MYOSINS
FOLDING PROJECT #12296 PROFILE

This project explores how blebbistatin, a drug, affects muscle protein (myosin). Myosin powers muscle movement. Blebbistatin stops myosin from working properly by blocking a step in its cycle. Scientists are using computer simulations to see how blebbistatin changes the shape of myosin and understand its effects better. This could lead to new drugs 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 the function of myosin.

Blebbistatin is a molecule used to inhibit myosin, a protein crucial for muscle contraction. It works by binding to myosin and preventing it from releasing phosphate, a step necessary for the protein to cycle through its function. This has implications for studying muscle diseases and potential drug development.

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Myosin

A type of motor protein responsible for muscle contraction and other cellular movements.

Myosin is a protein found in cells that plays a vital role in movement. It works by binding to actin filaments and pulling them together, causing muscle fibers to contract. Myosin also has roles in processes like cell division and transport within cells.

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ATP

Adenosine Tri-Phosphate

ATP is the primary energy currency of cells. It's a molecule that stores and releases energy through the breaking of its phosphate bonds. Cells use ATP for many processes, including muscle contraction, protein synthesis, and nerve impulse transmission.

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ADP

Adenosine Di-Phosphate

ADP is a molecule that is produced when ATP loses one of its phosphate groups. Cells use ADP to make ATP again through processes like cellular respiration.

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Actin

A protein that forms microfilaments, essential for cell structure and movement.

Actin is a protein that plays a critical role in cell structure and movement. It forms long, thin filaments called microfilaments, which are involved in processes like muscle contraction, cell division, and the transport of materials within cells.

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Hypertrophic Cardiomyopathy

A genetic heart disease characterized by thickening of the heart muscle.

Hypertrophic cardiomyopathy is a hereditary condition where the heart muscle becomes abnormally thick. This thickening can make it harder for the heart to pump blood effectively, leading to symptoms like shortness of breath, chest pain, and fainting.