Prace Call: 17th
ID: 2018184332, Leader: Michele Vendruscolo
Affiliation: University of Cambridge, UK
Research Field: BiochemistryBioinformatics and Life sciences
Collaborators: Gabriella Heller University of Cambridge UK , Thomas Löhr University of Cambridge UK
Resource Awarded: 28 Mil. core hours on MareNostrum
Alzheimer’s disease is the most common cause of dementia, but no cure is currently available to treat it. One of the hallmarks of this disease is the formation of neurotoxic plaques through the aggregation of the intrinsically disordered amyloid-β (Aβ) peptide. Decades of experimental studies have elucidated some of the mechanisms behind this aggregation process, but it is becoming increasingly clear that computational approaches can uniquely provide the atomic-level information required to define the detailed molecular events underlying Aβ aggregation and its inhibition. Recently, by applying novel drug discovery approach based on chemical kinetics, we discovered several small molecules able to suppress key microscopic steps in Aβ aggregation by binding the monomeric form of the protein. The availability of these small molecules provides an unprecedented opportunity to clarify which of their chemical features are responsible for their effects on Aβ aggregation, which in turn will create new opportunities for the rational design of more potent inhibitors. To exploit this opportunity, we propose to use molecular dynamics simulations using state-of-the-art enhanced sampling algorithms and experimental restraints to study how these small molecules modulate the structural properties of Aβ, which, being intrinsically disordered, should be described as a structural ensemble, in which each structure is assigned a distinct probability of occuring. As there are no experimental methods that can achieve the required accuracy, molecular dynamics simulations are currently the most effective way to obtain this atomic-level information of conformational ensembles of intrinsically disordered proteins. The accuracy required to characterise their modulation by small molecules is only currently possible using large computational resources. The availability of these offer us the unprecedented opportunity to simulate up to 100 molecules interacting with monomeric Aβ. Taken together, these simulations will help us elucidate the complex mechanism by which small molecules can interact with disordered proteins towards drug discovery for Alzheimer’s disease.