Heart attacks and strokes are two of the most typical causes of death in industrial nations today. They result from atherosclerosis, where plaques form in a coronary artery. The first stage of thiscomplex process is the accumulation of excess low density lipoproteins (LDLs), particles also known as “bad cholesterol",
in the artery wall, which then undergo chemical changes.

“To better understand how related diseases could be prevented, one first has to understand the structure and functions of LDL. This has been the essence of our research,” says Professor Ilpo Vattulainen, the principal investigator in the LIPOS (Lipoprotein Structure and Dynamics) research project.

The work is being carried out by the Department of Physics at Tampere University of Technology in Finland, the Wihuri Research Institute in Finland, the University of Groningen in the Netherlands and the University of Western Ontario in Canada.

Research in almost atomic detail

The objective of the research was to determine the structure of low density lipoproteins. LDL is the particle transporting cholesterol and its esters to cells, so an elevated concentration of LDL correlates to an increased risk of certain diseases, such as atherosclerosis.

“There are substantial difficulties associated with understanding how cholesterol-related diseases emerge, or even the functions of individual LDL particles. The functions of proteins depend on their structure and the structure of LDL is not well understood,” explains Vattulainen.

This is largely due to their small size – only around 20 nm. Experimentally, it is particularly challenging to probe the structure of LDL and related phenomena over such small scales. However, atomistic and coarse-grained simulation techniques provide an excellent means of analysing molecular systems in almost
atomic detail, hence complementing experiments.

“We paid particular attention to clarifying the role of lipids in the core particle of LDL, and their effect on the structure and dynamics of the protein sequence that surrounds it,” Vattulainen notes.

Impressive results create new opportunities

The LIPOS research project began in the autumn of 2007, and following major surveys and background studies, the initial models for LDL particles were ready in spring 2008. Simulations using the initial models were started around May 2008 and were completed in the autumn of that year.

“The analysis is still partly in progress, but the first articles describing the main findings are already almost complete,” Vattulainen says.

And what were the main findings of the research?

“It provided a great deal of insight into the distribution and dynamics of lipids inside LDL, and the effects of lipids on the structure of the protein sequence wrapped around LDL. In essence, we now know the structure of native LDL in almost atomic detail,” Vattulainen explains.

The research and its results also create the opportunity for further work, in order to gain greater understanding of the overall function of LDL particles.

“The results allow us to initiate an intriguing sequence of further studies, looking at how LDL particles interact, for example, with certain enzymes, oxidative agents and sugars that are involved in the chemical alterations of LDL and the consequent formation of cholesterol plaques.”

Pioneering studies with the help of DEISA

The LIPOS project has broken new ground in its field of science because the research method was truly unique.

“Previously, there have been no attempts at atomistic or coarse-grained simulations of LDL particles. In this respect, our study is pioneering as it is the first case in which LDL particles have been explored through simulations with full molecular detail,” Vattulainen says.

An important factor in the success of the research project was the supercomputing resources made available through the DEISA framework.

“DEISA allowed us to carry out an extensive, state-of-the-art simulation project for a molecular entity that is biologically particularly relevant. Large-scale parallel simulations for a system of this kind would not have been possible without resources of this calibre.”

The benefits of DEISA were, in Vattulainen’s view, obvious.

“There are only a handful of places in Europe that provide access to supercomputing resources of this size. Networking in this manner provides major added value for Europe overall,” Vattulainen comments.

Sanna Pyysalo