Modelling the Crystallisation and Physical Properties of Cholesterol Deposits

模拟胆固醇沉积物的结晶和物理性质

• 批准号: EP/H00341X/1
• 负责人: David Quigley
• 金额: $ 115.75万
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FH00341X%2F1
• 关键词: Modelling; Crystallisation; Physical; Properties; Cholesterol

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.

该研究项目将适应和扩展计算机模拟的最新技术，以模拟生物有害胆固醇沉积物的形成。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在确定动脉斑块稳定性方面是重要的。不稳定的斑块会破裂，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有力的手段，将分子水平上的模型与真实的材料的物理性质联系起来。有关纳米结构和组成的研究，以散装性能越来越普遍。一个重要但不太容易理解的问题是材料（特别是晶体）如何生长，并引入缺陷和杂质。这些缺陷会极大地改变物理性能，如强度和柔韧性。环境和化学因素，如温度和pH值，也可以通过有利于一种晶体结构（多晶型）的生长而影响生长材料。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。长期目标是通过分子模拟中可以表示的数量，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相关联。晶体胆固醇也是胆结石的主要成分。这项研究将开发的模拟技术有可能研究具有潜在医学应用的结石生长抑制剂。达到这一目标将需要开发新的模拟方法。晶体的生长，无论是从液体中冻结或从溶液中沉积，都是通过成核和生长过程进行的。成核是物质自发地排列成“种子”，晶体可以从中生长。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。模拟这些事件是极其困难的，并且仅针对少数材料完成，通常是在不现实的环境中构建以增强固体的形成。另一种方法涉及在模拟中引入有意的偏差或选择性，这会促进成核的某些特征。拟议的研究将采取这种方法。尽管该领域最近取得了一些进展，但柔性分子的结晶尚未被模拟。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构型。因此，这项研究需要结合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，以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。这项研究将最终在一系列大规模模拟使用世界一流的HECToR超级计算设施。这些将产生在仔细控制的生物环境中胆固醇沉积物结晶的数据，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，从而实现了解斑块破裂和结石形成的总体目标。

项目成果

The Question of cis versus trans Configuration in Octahedral Metal Diketonates: An In-Depth Investigation on Diorganobis(4-acyl-5-pyrazolonato)tin(IV) Complexes

八面体金属二酮中的顺式与反式构型问题：二有机双(4-酰基-5-吡唑啉酮)锡(IV)配合物的深入研究

• DOI: 10.1002/ejic.201101050
• 发表时间: 2012
• 期刊: European Journal of Inorganic Chemistry
• 影响因子: 2.3
• 作者: Caruso F

Effect of oxygen and nitrogen functionalization on the physical and electronic structure of graphene

• DOI: 10.1007/s12274-015-0768-0
• 发表时间: 2015-08-01
• 期刊: NANO RESEARCH
• 影响因子: 9.9
• 作者: Marsden, Alexander J.;Brommer, Peter;Wilson, Neil R.
• 通讯作者: Wilson, Neil R.

Stable prenucleation mineral clusters are liquid-like ionic polymers.

• DOI: 10.1038/ncomms1604
• 发表时间: 2011-12-20
• 期刊: Nature communications
• 影响因子: 16.6

Enhancement of island size by dynamic substrate disorder in simulations of graphene growth.

• DOI: 10.1039/c6cp00788k
• 发表时间: 2016-06
• 期刊: Physical chemistry chemical physics : PCCP
• 作者: Gwilym Enstone;P. Brommer;D. Quigley;Gavin R Bell

Accurate free energy methods for model organic solids

有机固体模型的准确自由能方法

• 发表时间: 2014
• 作者: Bridgwater Sally