Modelling the Crystallisation and Physical Properties of Cholesterol Deposits

Lead Research Organisation: University of Warwick
Department Name: Physics


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.


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Description We have extended state-of-the art computational methods for characterizing the stability of solid structures to crystals containing flexible molecular units. This has been applied to phase transitions in simple model systems as well as models for crystalline cholesterol. The tools and expertise developed have also been used to collaboratively address questions in a number of other systems, particularly ice formation, the prototypical crystal nucleation and growth problem.

We have also developed computational tools and molecular simulation software to accurately quantify the nucleation rate of flexible crystals from the melt, demonstrating that secondary and subsequent nucleation rates are orders of magnitude higher than the single primary rate computed in similar studies.

Work funded under this grant via the "New Directions for EPSRC Research Leaders" scheme has developed software for quantitative comparison of band structures to photoemission experiments and accurately quantified the role of nitrogen, oxygen and growth defects in graphene in determining its electronic structure.
Exploitation Route We hope that future research into small molecular crystallization, both in the context of crystallization disease and in pharmaceuticals can benefit from enhanced characterizations of phase stability in model systems, and the ability to predict crystallization rates using more detailed information that the primary nucleation rate.
Sectors Electronics,Healthcare,Pharmaceuticals and Medical Biotechnology

Title bs_sc2pc 
Description This programme performs "band structure unfolding", i.e. projecting the electronic structure of a defective or multi-component system into the primitive cell of the perfect/sub structure, primarily to compare with ARPES experiments. It interfaces to (and requires) CASTEP, the UK flagship code for plane-wave density functional theory. 
Type Of Technology Software 
Year Produced 2014 
Impact A number of projects in our group (publications pending) have used this tool to study the band structure of functionalised and substrate-supported graphene. The software is available to all UK academic license holders of CASTEP via CCPForge.