Reliable computational prediction of molecular assembly

An important modern frontier of research in the physical sciences is the proper understanding and control over molecular assembly. The Grand Challenge of "Directed Assembly of Extended Structures with Targeted Properties" tackles this frontier from various angles. I focus on the angle of chemical computing, which has established itself as an independent source of information, complementary to experiment. There is a need, of ever increasing urgency, for accurate and hence more reliable prediction of interaction energies between molecules. The structure and dynamics of molecular assemblies sensitively depend on most subtle energy changes. This is why the scientific challenge of accurate energy prediction is still as acute as ever. If energy is correctly predicted then everything else follows: realistic structures, dynamics and properties. I propose a novel approach, drastically different to the current paradigm.

Matter at ambient conditions is governed by a master equation called the Schrödinger equation, which returns the interaction energy of a molecular assembly. Solving this master equation accurately for sizeable molecular aggregates is very expensive or even impossible with current computer power. Force fields, however, can provide this interaction energy, and do so many orders of magnitude faster. A force field is a formula that delivers the energy of a molecular system as a direct function of the system's atomic coordinates. This formula contains many parameters, specific to the system at hand. The challenge is to design a force field that is reliable. The best and only long term strategy is to map the force field as faithfully as possible onto the solution of the Schrödinger equation, both in terms of energy and the wave function. With exascale computers around the corner and GPU technology recently overtaking CPUs, it is pivotal and timely to invest into more realistic force fields.

Here I aim to offer biomolecular modelling a completely new route to designing a force field, with much more truthful electrostatics. We propose the completed construction of the first ever (high-rank) multipolar force field for flexible molecules, with both intra- and intermolecular polarisation. This is crucial for molecular assembly and recognition, as well as the realistic modelling of hydrogen bonding. Molecular systems, in the presence of the strong and inhomogeneous electric fields caused by ions, will also be modelled realistically for the first time.

The true predictive power of a force field depends on the reliability of the information transfer of small molecules (or molecular clusters) to large molecules. Only if this transferability is high, a force field will make reliable predictions. The main idea behind our force field, called QCTFF, is to construct "knowledgeable" atoms. These atoms are drawn from small molecules and made to interact in order to predict properties of large molecules. They are 3D fragments of electron density, with a finite volume. These atoms have sharp boundaries, which endows them with a "malleable" character. Their precise shape responds to the immediate environment of the molecule they are part of. A machine learning method then captures how these atoms change their multipole moments in response to the positions of their neighbours. We have successfully reached the proof-of-concept stage of this novel idea and now I intend to fully exploit it.

Although QCTFF is generic, its application is biased towards proteins, ions and water. Only a fellowship can deliver the ambitious but feasible goal of creating this transformative enabling technology towards life science applications. This technology will also serve as a robust platform from which to develop an innovative novel force field, to study reactions in solution and in enzymes, as well as crystal nucleation. The radical and innovating decisions taken at the outset of QCTFF's design are the best guarantee for its long lasting success.

(A) Who will benefit from this research?
(A1) Exascale computing, the new frontier.
Exascale computing refers to computing capabilities beyond the currently existing petascale, representing a thousandfold increase over that scale. Last autumn, substantial government funding has been directly allocated to Daresbury Laboratories for investment into their own exascale computing facilities. We plan to have a version of QCTFF ready for testing on this facility before the middle of the Fellowship's duration. The higher computational cost of QCTFF will be offset by its enhanced realism and accuracy. The alternative of running current force fields on the exascale infrastructure would just entail that "unreliable results are obtained faster".

(A2) EPSRC itself and Policy-makers
On p.16 of the last International Review of UK Chemistry Research (2009), reviewers complain that "In the area of theory and computation, no provision seems to have been made to encourage the development of new algorithms and new ideas to bring to full fruition the utilisation of the next generation ... machines". The current application will raise the international standing of theoretical and computational chemistry in Britain. This will benefit EPSRC at their next international review.

(A3) Companies using molecular modelling.
Many companies recognise the increasing role of computation in their future because cheaper hardware is guaranteed to emerge during the coming decades. As users of more reliable software, companies will make better predictions, which enhances the trustworthiness of molecular modelling in experimentalist circles.

(A4) UK plc and employment.
In time of economic contraction it is important to invest into novel technologies. The invenion of a more reliable atomic modelling tool provides the basis for long term success and hence sustainable wealth creation. According to a market assessment we commissioned in connection with a different grant, molecular modelling methods are quoted as having become significant tools in nanoscale R&D across a variety of industries, including commodity and specialty chemicals, fuels, polymers, structured materials, electronics and photonics materials, industrial gases, personal care and food products, computer software and hardware and agricultural chemicals.

(A5) Academic researchers.
Details see Je-S box "Academic Beneficiaries".

(B) How will they benefit from this research?
The most important aspect is that we aim for a future-proof force field, that is, one that "works for the right reasons". If scientific work is carefully done then its product puts one in a strong position to have others benefit from it. The development of accurate intermolecular potentials is a strong research theme in Britain with seminal contributions from distinguished researchers. The requested fellowship will aim at strengthening this activity.

The impact of simulation on society in general is increasing at accelerated pace via the enhanced industrial application of molecular software. The current minister for Universities and Science is fully aware of this. He has announced a £145 million investment for innovation in e-infrastructure (details see National Importance section in Case for Support). The continuing reduction of hardware cost enables and therefore warrants the use of the more sophisticated models that this proposal provides. Industry widely recognises that the role of computation will increase in the future since cheaper hardware is guaranteed to emerge. However, computers are only as useful as the quality of the algorithms that run on them. The longer term impact of better software cannot be overestimated since it will enhance confidence in simulation.