Intrinsically Multifunctional Energy Landscapes: A New Paradigm for Molecular Design

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This project aims to advance theory and computer simulation to understand and design molecules capable of functioning as nanoscale devices. The inspiration comes from a recent study of an "intrinsically disordered" protein, which suggests new design principles for systems that can be switched in a controlled fashion between alternative configurations. The underlying theoretical framework is based on analysis of the potential energy landscape, which defines the variation of potential energy with particle positions for any molecular or condensed matter system. In particular, we formulate observable properties in terms of local minima on the energy landscape, and the transition states and pathways that connect them. Within a well-defined set of approximations, this view reduces the corresponding computational framework largely to geometry optimisation. The results are translated into experimental observables using the tools of statistical mechanics and unimolecular rate theory. The applications will address two Priority Areas: nanoscale design of functional materials, and understanding of biological processes. In previous work, we have established that systems with self-organising properties are associated with funnelled potential energy landscapes, where configurations are guided downhill towards a target morphology. This paradigm establishes a universality class, which includes magic number clusters (such as buckminsterfullerene), crystallisation, self-assembly, and protein folding. The realisation that intrinsically disordered proteins define an alternative class of behaviour leads us to consider a new paradigm for multifunctional systems. The research hypothesis addressed in the present proposal is that multifunctional molecules are associated with multifunnel energy landscapes. Understanding how naturally occurring systems exploit this capability, for example to bind different ligands, will provide design principles for artificial nanodevices that are switchable between alternative structures.Project goals will be achieved through a series of work packages:(1) Recent advances in methodology will be exploited to access experimental time and length scales. Implementing the corresponding computer programs on graphics processing units can provide efficiency gains exceeding two orders of magnitude. A variety of new ideas to further transform the sampling will be implemented and tested. (2) Intrinsically disordered proteins can perform multiple cellular functions by binding different partners. We aim to test the hypothesis that multiple functions are associated with an intrinsically multifunnel potential energy landscape. The focussing effect of binding partners on the structure of the landscape will be examined for two particular proteins.(3) The evolution of specificity for antibodies in the presence of antigens will be analysed in terms of the underlying landscape. Structure prediction and the effect of antigen binding and successive mutation will be related to changes in dynamics.(4) Multifunnel landscapes will be investigated for nucleic acids. Competition between G-quadruplex structures is predicted to result in alternative morphologies separated by high barriers, which may represent important targets for drug discovery. Design principles for ultraresponsive DNA-based devices will be deduced for structures that incorporate fast-folding segments.(5) The insight gained in the above projects will be used to design artificial nanodevices. Here we will consider switching via both external conditions, such as applied fields, and internal degrees of freedom that are accessible experimentally. For example, devices based upon helix inversion have the potential to couple linear and rotatory motion. To exploit this possibility we will design a photoswitchable chiral ligand. Transitions between the B and Z forms of DNA can also provide a route to nanoscale switches.