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.

Sulfonyl units, that is the -SO2- arrangement of atoms, are functional groups that feature in a significant number of pharmaceuticals, argochemcials and materials. Variations in which one or more oxygen atoms of these groups are replaced with nitrogen atoms are also emerging as useful molecules for exploring biological processes. This proposal is focused on this latter class of compounds. The types of molecules this encompasses - primarily sulfoximines and sulfonimidamides - are less explored than then non-aza-equivalent, and this is largely due to the lack of convenient methods for their preparation. Conventional syntheses of these types of molecules usually involve three or four synthetic operations, and often feature low-yielding steps. The chemistry involved also limits the substrates that can be converted to aza-sulfonyl-containing molecules. This proposal seeks to develop new reagents and new reactions to this class of molecules; the proposed chemistry will be achieved in a single operation, employ readily available reagents and substrates, and be conducted under mild conditions. The key aspect of the proposal is the design of new nitrogen-containing reagents that will allow ready access to a little used class of reactive intermediates; sulfinylnitrenes. By delivering these reactive intermediates in a simple way, using readily available reagents, a host of new reactivity, and thus transformations, will be available. These reactions will be used to provide general routes to sulfoximines and sulfonimidamides, as well as primary sulfonamides. We will deliver user-friendly reactions. These transformations will significantly simplify the preparation of these molecules, and allow them to be routinely considered when new collections of molecules for biological evaluation are being designed. We will seek to make the reagents we develop commercially available, thus allowing the rapid take-up of the methods we develop.

Chemical synthesis underpins our society in general - whether in the production of medicines, household or personal care items or for heat and power. The process of discovering a new molecule and taking it through to production scale remains a challenge, despite centuries of experience. The conditions of small scale discovery can be very different to those at the scales required to bring the new chemical product to wider society. Reducing this time may mean bringing drugs to market earlier, or providing more environmentally friendly alternatives to existing products. A digital twin is a representation of a physical process within a computational framework, allowing virtual experimentation to be carried out to assess the best set of conditions under which to run processes. These conditions can be selected and weighted towards (for example) the most environmentally friendly process, or the cheapest - depending on the wider demands of society. A digital twin also allows this to be addressed dynamically. This project develops the framework for building digital twins. As all chemical processes are different, and depend very much on the particular synthesis, we have to first learn something about our specific reaction. This will be carried out at the small scale under computer control, to narrow down the wide range of conditions (e.g. temperatures, concentrations, choice of catalysts used to speed up the reaction) for the process. This information then informs our digital twin model. At larger scale conditions vary through the reactor - dealing with many thousands of litres of material is very different to dealing with the small quantities at the discovery scale. Now we have gradients of temperature, material is much more poorly mixed - these can all influence the reaction. So we take our knowledge of these variations, which includes running flow simulations, and map onto it the information from our small scale tests. We can select which reactors we want to use, and their conditions that they are run under and make decisions about the overall process - just as before, driving it through questions of sustainability, cost, material purity. This gives us a framework that spans the physical development of material with a digital representation. We can explore a much wider parameter space than ever possible through experimentation, and assess the entire process digitally. This brings unprecedented agility to the manufacturing of products. The project builds on the world-class research that exists in the UK in automated tools used for self-optimising reactor systems and has a range of industrial partners spanning pharmaceuticals; AstraZeneca, Pfizer and UCB Pharma, and reactor control software experts; Perceptive Engineering, ensuring the barriers to adoption by industry of the approach developed in this project are minimised.

There is tremendous future scope for biomolecular simulation to provide unprecedented insights into biomolecular systems. The level of detail afforded by these methods, along with their ability to rationalise experimental data and their predictive power are already enabling them to make significant contributions in a wide variety of areas that are crucial for healthcare, quality of life and the environment. The UK biomolecular simulation community has a strong international reputation, with world-leading efforts in in drug design and development, biocatalysis, bionano-technology, chemical biology and medicine. HECBioSim has already delivered outstanding research with impact in bionanotechology, drug design and AMR. But we have only just scratched the surface and there is currently huge room for expansion. Having access to the largest, most modern computing facilities is essential for this. Renewal of the Consortium will enable us to continue allocating time ARCHER for cutting-edge biomolecular simulations. We will place a special emphasis on reaching out to experimentalists and scientists working in industry in order to foster interactions between computational and experimental scientists, and academia and industry to encourage integrated multidisciplinary studies of key problems. Biomolecular simulation and modelling is an integral part of drug design and development. The pharmaceutical industry needs well-trained scientists in this area, as well as the development of new methods (e.g. for prediction of drug binding affinities, ligand selectivity and metabolism). Members of the consortium have a strong track record of collaboration with industry to deliver trained scientists and new methodologies. For example, PhD students trained by consortium members have recently taken up positions in UCB, Unilever, Oxford Nanoimaging and even Sky Broadcasting as software developer. Many of these academic-industry collaborations have been strengthened by work done through HECBioSim allocations. The Consortium will continue to welcome new members from across the whole community. We will continue to develop computational tools and training for both experts and non-experts using biomolecular simulation on HEC resources. We propose to develop new tools that will enable inter-conversion between biomolecular systems at different levels of resolution thereby allowing users to tackle more ambitious 'grand challenges' than are currently feasible. In summary HECBioSim will foster collaborations between computational and experimental scientists between scientists working in industry and academia in all disciplines within biomolecular simulation to maintain the UK as a world-leader in this field.