RESEARCH: CANCER
FOLDING PROJECT #17646 PROFILE

Drug discovery for diseases like cancer is hard because we need to find new shapes that drugs can bind to. This project tests different ways to start computer simulations so we can find these shapes faster and more efficiently. It's like giving computers multiple starting points to explore a maze, increasing the chances of finding the right path.

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

In drug discovery, particularly that of cancer, maximizing state exploration is a useful novel strategy – providing new protein states and conformations to point drug design methods at increases the likelihood that a potential binder and inhibitor may be found. However, in many cases a new state that is "useful for design" (ie.

ones distinct enough to be worth targeting to identify novel drugs) require a lot of sampling or simulation.

Sometimes, even exascale computers like Folding@home are not enough! Adaptive methods are very powerful here, but have the drawback of requiring system knowledge, or having to guess which protein features are worth adaptively exploring on, which may not always turn out to be true. Identifying druggable states or exploring conformational state space relevant to disease is an existing challenge.

The embarassingly parallel nature of Folding@home allows us to massively scale up our exploration.

However, the underlying methods still rely on luck to a large extent – we must discover the states in work units as the dataset grows in size and more work units are run.

This can be an incredibly inefficient process, wasting work units on regions of state space that are irrelevant or uninteresting to the question at hand.

Adaptive Seeding is a way to tackle this inefficiency.

Rather than applying a "boost" potential that alters the physics of our system, or having to do live-streamed analysis like Adaptive sampling, Adaptive Seeding sets up multiple starting structures across conformational space.

The intention is that having multiple distinct starting structures will increase the rate at which the landscape is traversed and lead to transitions/pathways connecting functional states in less simulation time, while preserving physics.

These projects seek to test different "seeding" approaches that yielded a different spread of starting structures.

Each unique structure starts at a different RUN.

As with other projects, we will be studying MET kinase.

17645: Run using starting structures generated using AI-methods like AlphaFold2
17646: Run using starting structures that are stemmed from "fixing" experimentally derived structures in the PDB.

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drug discovery

The process of identifying and developing new medications.

Drug discovery is the complex process scientists use to find and develop new medicines. It involves many steps, from identifying a potential drug target (like a specific protein) to testing the drug in humans to make sure it's safe and effective.

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cancer

A group of diseases characterized by the uncontrolled growth and spread of abnormal cells.

Cancer is a serious illness where cells grow out of control. These abnormal cells can invade nearby tissues and spread to other parts of the body. There are many different types of cancer, each with its own characteristics and treatments.

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protein

Large biomolecules essential for the structure and function of all living organisms.

Proteins are the workhorses of our bodies. They are made up of long chains of smaller units called amino acids. Proteins have many important functions, such as building tissues, transporting molecules, and catalyzing chemical reactions.

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drug design

The process of designing and developing new drugs that target specific biological molecules.

Drug design is a complex process that involves understanding how diseases work at the molecular level. Scientists use this knowledge to create drugs that can interfere with harmful processes in the body.

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inhibitor

A substance that reduces the activity of a particular enzyme or biological process.

Inhibitors are molecules that can block or slow down the action of other molecules. They are often used in medicine to treat diseases by inhibiting the activity of harmful enzymes.

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simulation

The process of creating a computer model to mimic a real-world system or phenomenon.

Simulation involves using computers to create virtual representations of things like physical systems, biological processes, or even entire societies. This allows researchers to study complex phenomena in a controlled environment.

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Folding@home

A distributed computing project that uses volunteered computer processing power to simulate protein folding.

Folding@home is a global effort to use the power of many computers to study how proteins fold. Proteins are essential for life, and understanding how they fold can help us develop new drugs and treatments for diseases.

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Adaptive Seeding

A method for enhancing protein folding simulations by starting with multiple diverse initial structures.

Adaptive Seeding is a technique used to improve the efficiency of protein folding simulations. By starting with different initial protein structures, researchers can explore a wider range of possible folding pathways and find the most energetically favorable conformation.