Name: Sarah Harris
Institution: University of Leeds
Research: Computer Simulations of Biological Molecules at the Atomic Level
Biomolecules are soft, nanoscale objects which continuously change shape due to thermal motion. This flexibility is often critical to their function in the cell. For example, when two biomolecules bind to each other to transfer biological information, or to instigate a chemical reaction required by the metabolism of the cell, there are frequently very large changes in shape which allow the molecules to maximise the fit between them.
Although structural biologists have been highly successful in determining the average shape of biomolecules at the atomic level, it is far more difficult to study biomolecular flexibility. The experimental information that researchers generally obtain only provides a static snapshot of a system that in reality is highly dynamic.
Sarah’s team hope to understand how biological molecules perform their functions by using high performance computer simulation. They use this to study how individual proteins and DNA molecules move in response to thermal effects and how their shape changes when forces are applied. The chemical complexity of biological molecules means that these calculations are extremely computationally expensive so state of the art resources, such as the NGS, are required for the calculations.
Sarah works on a range of projects including the development of new methods to quantify the importance of dynamics for in silico drug design, studying charge transfer through DNA for nanotechnological applications and using computer simulation to determine how the compaction of DNA into the relatively small nuclear region might be used by the cell to actually control genes, as well as package them.
Most recently, she has used high performance computing to study the fragmentation of long filamentous structures formed from aggregated proteins which are known as amyloid fibrils. These are associated with a number of degenerative diseases in humans including Alzheimer’s, Parkinson’s and type II diabetes.
Recent biochemical studies have shown that if the fibrils are broken up into short fragments through stirring, then their toxicity increases. However, since these experiments are not able to provide any information about breakage events at the atomic level, she has used atomistic modelling to apply sufficient force to an amyloid fibril in silico so that it fragments into two or more separate parts. Her calculations show that the fibrils are more fragile if they contain structural defects at the molecular level as these defects act as weak points that are prone to failure.
These simulations suggest a possible molecular explanation for the increased fragility of certain types of amyloid fibril, and have implications in the development of amyloid disease states. All of these calculations use readily available academic computer codes such as AMBER, NAMD and GROMACS which have been designed to take advantage of parallel architectures such as the NGS and scale well up to ~500 processors, depending on the size of the system. Most of the teams calculations, however, use between 16 and 64 cores.
Sarah explained “The NGS has provided us with additional computational resources which have enabled us to perform more accurate calculations than would otherwise have been possible. It has also acted as a nucleation point for researchers using high performance computing in the UK. This exchange of ideas has lead to our research group considering new ways in which we can perform our calculations more efficiently and on a far larger scale in the future”.
PI - Dr Sarah Harris (EPSRC grant); Prof Tony Maxwell John Innes Centre (BBSRC grant).
Funding body - EPSRC (EP/DO53102/1), EPSRC CASE award with AstraZeneca and BBSRC (BB/IO19472/1).
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