Predictive modelling of ligand binding to flexible proteins

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It is now recognised that a large fraction of the human proteome is made of extremely flexible proteins whose structure cannot be characterized by a unique fold. These intrinsically disordered proteins (IDPs) play key roles in cells and have been implicated in a striking range of diseases such as cancers, neurodegenerative disorders and diabetes. These diseases will become increasingly prevalent in an aging UK population. It is therefore highly desirable to develop small drug-like molecules that could bind to IDPs and modulate their function. Yet it is very difficult to determine the range and nature of conformations adopted by an IDP using experimental techniques. IDPs are therefore generally considered "undruggable" by the pharmaceutical industry. It is important to develop new techniques and technologies to address the national and global health challenges caused by IDPs. Computer simulations have the potential to provide detailed structural models of IDP/small molecule interactions to guide rational structure-based drug design efforts. However standard simulation techniques are unable to perform this task. Their description of intermolecular interactions is too approximate. The exploration of the complicated energy landscape of IDPs is too time consuming. It is therefore essential to develop novel simulation methodologies that can handle the high flexibility of IDPs.We propose the development of new molecular simulation algorithms that will enable the rapid computation of the structural, thermodynamic and kinetic properties of IDPs in complex with drug-like molecules. Our research is structured around three objectives:1. We will develop a force-field optimisation method that iterates biased molecular dynamics simulations and energy reweighting to minimize systematic errors in the prediction of molecular observables for IDP/small molecule complexes (e.g. NMR chemical shifts). 2. We will develop a simulation method to steer "on-the-fly" computational efforts towards the exploration of molecular conformations that contribute the most to overall uncertainties in predicting the dynamics of IDP/small molecule complexes.3. We will perform simulation studies to elucidate the mechanisms of small molecule binding to selected IDPs. Such interactions currently challenge our understanding of molecular recognition. Test systems will include for instance the IDPs c-myc and p53 that play key roles in the progression of several cancers. The primary goal of this research is therefore to develop new computational methodologies that will enable preclinical drug discovery efforts to target intrinsically disordered proteins with structure-based approaches. In addition the algorithms and software developed during this research will be widely applicable and this research will also enable applications in a broad range of soft-condensed matter research areas.