G8 Multilateral Research Funding INGENIOUS

生物分子过程的动力学定义了许多生物医学技术，因此代表了很大一部分制药工业的基本基础。由于问题的复杂性，计算机模拟是唯一可以在所需的分辨率水平上捕获绑定机制的可用工具。事实上，在许多情况下，这些过程是非常短暂的，这使得它们很难通过实验检测到。可能是速率限制的中间络合物可以按数量级改变速率，使潜在的候选药物不起作用(反之亦然)。目前，只能通过昂贵且耗时的实验测试来检查这一点。因此，使用计算机模拟计算速率的可能性可以对药物设计研究产生非常重要的影响。将一组经典原子结合到连续介质溶剂(隐含溶剂)中的尝试早已为人所知。然而，描述结构连续体的最一致的方法是流体动力学，这是一个最近才变得活跃的方向。从概念上讲，在MD和CH区域重叠的“转移”区域(“失控的”MD粒子)模拟MD粒子仍然是几乎所有这类方法中最紧迫的问题。我们提出了一个全新的混合模型，旨在解决这个问题。它基于对磁通耦合方法中的MD和CH分量的一般性描述。所提出的框架将确保CH和MD表示之间的转换是平滑的，其特点是：(I)不存在诸如原子部分和连续部分之间的人为排斥势垒或添加新粒子的数字“固定”，(Ii)在整个系统体积中使用相同的方程统一处理解部分，(Iii)由单个经验函数完全控制，该经验函数在空间和时间上都可以是任意形式的。这种新的方法将大大降低模拟成本，这是由于对MD区域进行了大量的截断，而没有丢失MD区域中详细的原子模拟或质量和动量的宏观守恒定律。该项目是最先进的计算机硬件开发、先进的数值模拟(分子动力学、连续介质流体力学和数值方法的三合一)和生物医学重要分子系统的前沿研究的良好平衡的组合。

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.