Searching for ALS Cures Using Accelerated Protein Dynamics Simulations of TDP-43

Overview

Amyotrophic Lateral Sclerosis (ALS) is a deadly disease. Half of all sufferers die within 2 years of diagnosis, and 14 out of 15 will die within 10 years. In patients, ALS interferes with communication between the brain and muscles. Unused muscles then deteriorate, and when muscle wasting reaches the lungs and heart, the disease becomes fatal. Only recently have scientists begun to really understand what causes this tragic disease. It is increasingly believed that ALS results from shortage of functioning TDP-43 protein in the brain, which can be caused by unhealthy TDP-43 clumping into sticky fibrils that bind healthy TDP-43. Knowing this, our project tries to answer whether it is possible to find medicinal molecules that can prevent healthy TDP-43 from sticking to fibrils? We think so, and we have used long duration accelerated molecular dynamics simulations over many microseconds to test two hypotheses: 1. molecules that bind to the right part of healthy TDP-43 might make it more stable, and less likely to stick to the fibril, or 2. molecules that bind to unhealthy fibrils might make them less sticky. To address these hypotheses, we divided the project into two parts: a search for molecules that bind to TDP-43 in ways that make the healthy helix stronger and less likely to unwind, and the design of compounds that bind to the toxic ends of unhealthy TDP-43 fibrils to stop the chain reaction. In measuring unwanted TDP-43 to fibril binding, our results appear promising. While untreated TDP-43 gradually locks onto the fibril, our best fibril capping molecule (a tetrachloro peptide mimic) led to TDP-43 dropping completely away from the fibril. Our best helix stabilizer molecule (h013a) also helps the protein to gradually dissociate (losing 4 residue contacts during the simulation). To gauge medicinal effectiveness, we computed logP (blood solubility) and blood brain barrier permeability (to treat central nervous system disorders). To prevent unwanted side effects, we predicted general toxicity and simulated whether stabilizers might prevent DNA binding to TDP-43.

Competition history

• AJAS 2018 Category not listed

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