G8 Multilateral Research Funding INGENIOUS

The kinetics of biomolecular processes define many biomedical technologies and for this reason represent the fundamental basis for a large segment of pharmaceutical industries. Because of the problem complexity, computer simulations are the only available tool that can capture the mechanisms of binding at the required resolution level. Indeed, in many cases the processes are very short lived which makes them hardly detectable by experiment. Intermediate complexes that may be rate limiting can change the rates by orders of magnitudes rendering potential drug candidates inactive (or vice versa). Currently this can be checked only by expensive and time consuming experimental tests. Thus, the possibility of calculating the rates using computer simulation can make very significant impact on drug design studies.
Attempts of incorporating a group of classical atoms into a continuum solvent (implicit solvent) are known for a long time. However, the most consistent approach describing a structured continuum, the hydrodynamics, is a direction that becomes active only very recently. Conceptually, modelling the MD particles in the 'transfer' region where the MD and CH domains overlap (the 'runaway' MD particles) remains the most pressing problem of essentially all approaches of this type.
We propose a fundamentally new hybrid model that aims at solving this problem. It is based on a generalised description of the MD and CH components within the flux coupling approach. The proposed framework will ensure that the transition between the CH and MD representations is smooth and characterised by (i) the absence of numerical "fixes" such as artificial repulsive barriers between the atomistic and continuum parts or adding new particles, (ii) unified treatment of the solution parts using the same equations throughout the system's volume, (iii) the full control by a single empirical function that can be of arbitrary form both in space and time. The new method will lead to a large reduction of the simulation cost due to a large truncation of the MD domain, achieved without loosing either the detailed atomistic simulation in the MD zone or the macroscopic conservation laws for both mass and momentum.
The project is a well balanced combination of state of the art computer hardware development, advanced numerical modelling (the triad of molecular dynamics, continuum fluid mechanics, and numerical methods) and cutting edge investigation of biomedically important molecular system.

The project will cover three directions of research and technology that are among the most actively developed worldwide: high performance computing, methods for molecular modelling, and biomolecular simulation. The main outcome will be a new scalable computational complex consisting of advanced hardware and software tools for complex molecular dynamics / fluid simulations aiming to reach the exascale performance with applications in the interdisciplinary field of continuum fluid dynamics / molecular dynamics.
We expect that the new computational complex developed will be of a great interest for leading biomedical/pharmaceutical groups interested in long time high-resolution simulations such as, for example, HIV Inhibitors Protease binding or protein folding.
The mechanisms of ligand binding, one of the processes planned to be studied in the project, is fundamental for many biomedically important molecular functions. By predicting the rate limiting intermediates and thus facilitating or suppressing ligand binding the project will directly contribute to the investigations on the effectiveness of drug candidate molecules. Despite the wide spread of computer modelling techniques currently in use in drug development, their effectiveness is limited because of large number of poorly substantiated assumptions involved, while direct high-resolution simulations, until recently, have remained prohibitively expensive. Advances in computer hardware, hybrid molecular dynamics modelling and algorithms will make such simulations possible, and our project will contribute towards this important and actively developing area.
The project is expected to have a very substantial impact both economically and, in a long run, to a wider society outside the academia and industry. The former because the pharmaceutical companies involved in drug development will be able to significantly narrow down the spectrum of drug candidates which, in turn, will reduce the amount of very expensive and time-consuming experimental tests required. The wider impact of the project is expected because the project is aimed to assist the modern drug design process, and the latter has proven to be a very effective way of introducing new approaches in treatments of a wide variety of diseases. The project, therefore, will be eventually contributing to the improvement of the quality of life at an important fundamental level.
In addition to this, the project will produce 3 highly trained computational molecular scientists / fluid dynamics modellers who will make a further impact by disseminating the post-project results in their further work. The interdisciplinary character of the project and its high impact on commercial applications will provide them with a unique set of skills combining the fundamental scientific knowledge with very practical expertise in computer simulations, mathematical modelling and experiment.