Modelling the Crystallisation and Physical Properties of Cholesterol Deposits

该研究项目将适应和扩展计算机模拟技术的当前状态，以模拟生物有害胆固醇沉积的形成。各种形式的胆固醇构成了与冠心病相关的动脉斑块的重要组成部分。胆固醇沉积物的物理性质是决定动脉斑块稳定性的重要因素。不稳定的斑块可能破裂，导致心脏病发作或中风，因此是发达国家的主要死亡原因。计算机模拟提供了一种强大的手段，将模型在分子水平上与真实材料的物理性质联系起来。将纳米结构和组成与体性质联系起来的研究越来越普遍。一个重要但不易触及的问题是，包含缺陷和杂质的材料（尤其是晶体）是如何生长的。这些缺陷会极大地改变物理特性，如强度和柔韧性。环境和化学因素，如温度和pH值也会影响生长材料，有利于一种晶体结构（多晶型）的生长。因此，模拟沉积物的生长是了解这些因素和其他因素对所得材料的结构和组成的影响的有力工具。长期目标是将与心脏病发作和中风相关的临床风险因素与含有胆固醇晶体的沉积物的物理性质联系起来，通过分子模拟来表示数量。结晶胆固醇也是胆结石的主要成分。本研究将开发的模拟技术具有研究抑制结石生长的潜在医学应用的潜力。实现这一目标需要开发新的仿真方法。晶体的生长，无论是从液体中冻结还是从溶液中沉积，都是通过成核和生长的过程进行的。成核是物质自发排列成“种子”，晶体由此生长。这是一个真正的纳米级事件，直接导致肉眼可见的生长过程。模拟这些事件是非常困难的，并且只完成了少数材料，通常是在不现实的环境中构建，以增强固体的形成。另一种方法是在模拟中引入有意的偏置或选择性，从而促进成核的某些特征。拟议中的研究将采用这种方法。尽管该领域最近取得了一些进展，但柔性分子的结晶尚未得到模拟。胆固醇分子有一个灵活的尾巴，在胆固醇晶体的基本重复单元内采用几种不同的结构。因此，这项研究将需要纳入模拟有机分子构型之间罕见转变的工具。除了新的模拟方法外，这项研究还需要改进胆固醇模型，使其能够准确地再现因环境的细微变化而形成的不同固体。将研究和调整各种候选模型以适应现有数据。这项研究将在使用世界一流的赫克托超级计算设备的一系列大规模模拟中达到高潮。这些将产生在精心控制的生物环境中胆固醇沉积结晶的数据，可以与实验进行比较。生物环境对这些固体性质的影响将首次被计算出来，从而导致了解斑块破裂和结石形成的总体目标。

This research project will adapt and extend the current state of the art in computer simulation to model the formation of biologically harmful cholesterol deposits. Cholesterol in a variety of forms makes up a significant component of the arterial plaque associated with coronary heart disease. The physical properties of cholesterol deposits are important in determining arterial plaque stability. Unstable plaque can rupture, leading to heart attack or stroke and is hence the leading cause of death in the developed world.Computer simulation provides a powerful means to connect models at the molecular level with the physical properties of real materials. Studies relating nanoscale structure and composition to bulk properties are increasingly commonplace. An important, but less accessible question is that of how materials (and crystals in particular) grow, incorporating defects and impurities. These imperfections can drastically alter physical properties such as strength and flexibility. Environmental and chemical factors such as temperature and pH can also influence the growing material by favouring the growth of one crystal structure (polymorph) over another. Simulating the growth of deposits is therefore a powerful tool in understanding the influence of these and other factors on the structure and composition of the resulting material. A long term goal is to relate clinical risk factors associated with heart attack and stroke, via quantities which can be represented in molecular simulations, to the physical properties of deposits containing cholesterol crystals. Crystalline cholesterol is also a major constituent of gallstones. The simulation techniques this research will develop have the potential to study inhibitors to stone growth with potential medical applications.Reaching this goal will require development of new simulation methods. Growth of a crystal, by either freezing from a liquid or deposition from solution proceeds by a process of nucleation and growth. Nucleation is the spontaneous arrangement of matter into a 'seed' from which the crystal can grow. This is a true nanoscale event which directly leads to a growth process visible with the naked eye. Simulating these events is extremely difficult and has only been accomplished for a handful of materials, often in unrealistic environments constructed to enhance the formation of a solid. An alternative method involves introducing a deliberate bias or selectivity into the simulation which promotes certain signatures of nucleation. It is this approach the proposed research will take. Despite a number of recent developments in the field, crystallisation of flexible molecules has yet to be simulated. The cholesterol molecule has a flexible tail which adopts several different configurations within the basic repeating unit of cholesterol crystals. The research will therefore need to incorporate tools for simulating the rare transitions between configurations of organic molecules.In addition to new simulation methods, the research will require improved models of cholesterol which can accurately reproduce the different solids formed in response to subtle changes in environment. Various candidate models will be studied and adjusted to fit the available data. The research will culminate in a series of large scale simulations using the world class HECToR supercomputing facility. These will generate data on crystallisation of cholesterol deposits in carefully controlled biological environments which can be compared to experiment. The influence of the biological environment on the properties of these solids will then be calculable for the first time, leading toward the overall goal of understanding plaque rupture and stone formation.