Modelling the Crystallisation and Physical Properties of Cholesterol Deposits

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.