Cholesterol, while posing a potential threat to human health, is undeniably one of the most crucial small molecules in human physiology, playing a myriad of critical roles in biology and medicine. Its significance lies in its involvement in maintaining and regulating membrane fluidity, sterol interactions with lipids and proteins, and interactions between viruses and human cells. Moreover, cholesterol serves as a critical drug target.
Despite its importance, there is still much that remains unknown about cholesterol, particularly in terms of how these sterol molecules move and function within the cellular membrane of cells.
Scientists have been studying the movements and interactions of cholesterol in living systems for decades, but the exact molecular dynamics have remained elusive, partly due to limitations in studying commercially available sterols and the resolution of current solid-state nuclear magnetic resonance spectroscopy (SSNMR) techniques.
However, a recent breakthrough by researchers from the University of Illinois Urbana-Champaign and the University of Wisconsin-Madison has shed light on cholesterol's behavior at the atomistic level in cells. This breakthrough has the potential to have far-reaching implications for future studies on health and disease, according to the researchers.
In their study published in the Journal of the American Chemical Society, the team, led by biochemistry professor Chad M. Rienstra from the University of Wisconsin-Madison, and University of Illinois Urbana-Champaign chemistry professors Martin D. Burke and Taras V. Pogorelov, employed new advanced experimental and computational methods to capture how cholesterol molecules move within cell membranes.
Their approach included innovative SSNMR experiments, state-of-the-art all-atom molecular dynamics simulations, and quantum mechanical calculations on synthetic cholesterol in phospholipids.
Cholesterol, a major component of biological membranes that can be extracted from sources like eggs, is a 27-carbon compound with a structure that includes a tail made of hydrocarbons attached to a flat core consisting of four hydrocarbon rings.
For the first time, the researchers were able to label each carbon atom and design a protocol to investigate the atomistic dynamics, or motion and forces, on each atom. This enabled them to reveal an overall picture of how cholesterol moves within a membrane.
According to Taras V. Pogorelov, “Collectively these studies revealed that cholesterol displays segmental dynamic coupling between the fused rings and tail conformations. In particular, the movements of the tail and the whole molecule are correlated, while tails rotate in a ‘crankshaft manner.'”
Additionally, the researchers' closely knit experimental-computational workflow allowed them to identify and quantify the specific conformations that cholesterol assumes in the cell membranes.
The results of this study have broad implications for a better understanding of the function of sterols in living systems. Furthermore, the methods developed in this research open new possibilities for future studies on how cholesterol influences the functional dynamics of membrane proteins in both healthy and diseased states.
Source: University of Illinois at Urbana-Champaign