Predictive modelling of ligand binding to flexible proteins

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.

Immediate beneficiaries of this research are academic scientists with an interest in biophysical studies of intrinsically disordered proteins, either for fundamental basic science or for designing small molecule inhibitors as chemical probes or therapeutic agents. The current state-of-the art is to use structure-based approaches to design new chemical probes.

Successful completion of this research is also bound to generate substantial interest from the pharmaceutical/biotechnology industry in light of possible applications for industrial drug-discovery.

In the longer term, the widespread availability of the new technologies that have arisen from this research could help deliver new drug therapies and hence impact on a very large population that would benefit from improved health-care options.

The UK pharmaceutical industry contributes over £8 billion pounds to the UK's gross domestic product. Over the past decade research and development activities in the pharmaceutical industry have undergone dramatic changes. Part of the problem is that it is increasingly difficult to address unmet therapeutic needs with existing drug discovery technologies. New computational methodologies that enable routine characterization of the free energy landscape of intrinsically disordered proteins will provide precious structural information for drug designers and allow the use of structure-based drug design approaches to develop novel drug therapies against targets previously considered "undruggable". The research has thus the potential to contribute positively towards preclinical drug discovery efforts from the UK pharmaceutical and biotechnological industry. This would in turn boost the economic competitiveness of the UK.

Ultimately, improved ability to modulate the function of proteins implicated in diseases will translate into novel medicines for unmet therapeutic needs. Over a timescale of a few decades the proposed research has the potential to enhance the length and quality of life of the citizens of the United Kingdom and elsewhere in the world.

In order to maximize dissemination of research findings we have already taken steps to initiate multiple collaborations with scientists from a wide range of background and who share an interest in studies of intrinsically disordered proteins through computational or experimental methods. This increases the likelihood that from its early days the topics and ideas behind this research will be communicated to a broad audience of academic scientists, which might in turn influence their research plans.

We have also made plans to actively engage with scientists working in the UK pharmaceutical industry. Regular interactions either online or through face-to-face meetings will help ensure that our research objectives are compatible with high impact outcomes for the pharmaceutical industry. We will provide technical expertise and training to industrial scientists wishing to test on in-house data the software and protocols developed during this research.

The methodologies developed in this research will be disseminated through publications in leading international journals and presentations at international conferences. Research staff involved in this research may move on to careers in the industry where they could bring in the new technologies. The software to carry out research will be made widely available to academic and industrial scientists. A workshop will also be organised to facilitate training of academic and private research scientists.

This project fits in the ESPRC research areas "Computational and Theoretical chemistry" and "Chemical Biology and Biological Chemistry". The theme of this research is strongly aligned with the EPSRC challenge theme "Healthcare technologies" (sub-themes "Techniques for Biomedical Understanding" and "Therapeutic technologies"). This research will therefore contribute towards achieving EPSRC's pathways to impact.