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Computer modeling reveals behavior of individual lipid molecules

May 08, 2020

Lipids are essential building blocks of cell membranes, which control the exchange of substances and energy between a cell and its environment. Developed at the Moscow Institute of Physics and Technology, a new open-source software tool PCAlipids aims to analyze lipid behavior. The new program has been presented in a paper that comes out in print in the upcoming July 1 issue of Biochimica et Biophysica Acta -- Biomembranes.

Every living cell is surrounded by a membrane that serves a number of vital functions, from facilitating the uptake of materials essential for survival to controlling cell regulatory processes. What enables this wide range of functions is the unique structure of the membrane: almost rigid proteins incorporated in a flexible lipidic layer.

The lipid composition of membranes has been found to influence how the individual proteins and the membrane as a whole function, therefore emphasizing the importance of lipids. However, the exact molecular mechanism of lipid-protein interplay is yet to be uncovered. PCAlipids is an important step toward understanding that mechanism.

Ways to examine lipid-protein interplay in membranes

The studies of membrane proteins and lipids cannot rely on the same techniques. While a host of experimental methods are available to study protein functioning, they lack either temporal or spatial resolution for analyzing lipids. To close this gap, various computational techniques are employed.

One of them, molecular dynamics simulations, enable researchers to examine the dynamics of a molecular system with atomic precision and at a timescale of picoseconds, or trillionths of a second. In order to achieve biologically relevant temporal and spatial scales, the interatomic interactions of quantum nature are simplified to a classical representation. The method involves calculating the forces that act on each atom and solving the associated Newton's equations of motion. The set of parameters used to define interatomic forces is called a force field.

To make sure that force fields are reliable, they undergo validation: Simulation results are contrasted with actual experimental data. The force fields used to model the behavior of the protein-lipid systems in cell membranes require such validation, too. That defines the focus of the tools that aim to analyze the simulations of membrane systems: It is mainly the experimentally measurable quantities that are extracted from the simulations. Due to the limitations of experimental techniques, the currently used analyses focus on large groups of lipids, while the behavior of individual lipids does not get much attention.

New software to analyze individual lipids

Pavel Buslaev, Khalid Mustafin, and Ivan Gushchin from the MIPT Research Center for Molecular Mechanisms of Aging and Age-Related Diseases have developed an open-source script called PCAlipids that analyzes the structure of individual lipid molecules at a given moment and describes their conformational changes -- the reshaping of molecules. A method known as principal component analysis underlies the script.

"PCAlipids is a piece of software that enables describing the motion of an individual molecule. While our study focused on lipids, the method is applicable to other molecules as well," explained Buslaev, who is a researcher at the MIPT Laboratory of Structural Analysis and Engineering of Membrane Systems.

"As of now, it is not possible to experimentally measure the values analyzed by PCAlipids," he added. "However, we have proposed several experiments. Hopefully, this will lead to the development of a new experimental area. The resulting data could then be contrasted with simulated lipid behavior to refine model parameters."

PCAlipids first identifies groups of atoms moving together. Next, it defines a new basis, such that the first basis vector is associated with the collective motion that has the largest amplitude and involves the largest number of atoms. The second most important motion determines the second basis vector and so on.

The analysis that follows relies on the established basis and aims to determine the effects of various factors on the lipid molecules. For example, an additional compound can be introduced into the simulation. If that affects the first, most significant collective motions, it means the compound will have a major influence on the membrane. Otherwise, its impact will be low. The manner in which the collective motions are impacted can reveal the mechanisms behind the compound's effects.

Effects of temperature, cholesterol, and more on lipids

The team from MIPT used the new software to study the effects of temperature, cholesterol, and membrane curvature on individual lipids. These parameters have long been known to influence the behavior of the membrane as a whole, but it remained unknown how they affect individual molecules.

Lowering the temperature causes the membrane to undergo a phase transition: The lipids become largely ordered. PCAlipids helped to highlight the beginning of phase transition and quantitatively describe how the number of possible lipid structures varies as the freezing point is approached. It turned out that this number remains stable up until freezing, but the rate of transitions between these structures grows progressively slower.

Cholesterol is a crucial cell membrane component that promotes lipid ordering. PCAlipids revealed that the significant collective motions become more compact in the presence of cholesterol. The simulation also exposed the mechanism that mediates the effects of cholesterol on lipid ordering.

The cell membrane is flexible and tends to bend a lot, which is vital to its functioning. This leads to one membrane layer being convex and the other concave. Both configurations proved to accommodate the same range of possible lipid structures; however, the rate of transitions between different structures is noticeably higher in the convex layer.

The study has demonstrated that PCAlipids can be used to investigate the structure of lipid systems. The tool replicates the findings of prior research, but also reveals details that remained elusive up until now. This illustrates the potential of the new software developed at MIPT to provide insights into the processes that occur in cell membranes.
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The study reported in this story was supported by the Russian Foundation for Basic Research.

Moscow Institute of Physics and Technology

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