rsos.royalsocietypublishing.org Research Cite this article: Alsop RJ, Himbert S, Dhaliwal A, Schmalzl K and Rheinstädter MC. 2018 Aspirin locally disrupts the liquid-ordered phase. R. Soc. open sci. 5: 171710. http://dx.doi.org/10.1098/rsos.171710 Received: 24 October 2017 Accepted: 23 January 2018 Subject Category: Biochemistry and biophysics Subject Areas: biophysics Keywords: lipid membranes, cholesterol, aspirin, liquid-ordered phase, membrane–drug interactions Author for correspondence: Maikel C. Rheinstädter e-mail: rheinstadter@mcmaster.ca Electronic supplementary material is available online at https://dx.doi.org/10.6084/m9. fgshare.c.3998217. Aspirin locally disrupts the liquid-ordered phase Richard J. Alsop 1 , Sebastian Himbert 1 , Alexander Dhaliwal 1 , Karin Schmalzl 2 and Maikel C. Rheinstädter 1 1 Department of Physics and Astronomy, McMaster University, Hamilton, Ontario, Canada 2 JCNS, Forschungszentrum Jülich GmbH, Jülich Centre for Neutron Science at ILL, Grenoble, France MCR, 0000-0002-0558-7475 Local structure and dynamics of lipid membranes play an important role in membrane function. The diffusion of small molecules, the curvature of lipids around a protein and the existence of cholesterol-rich lipid domains (rafts) are examples for the membrane to serve as a functional interface. The collective fluctuations of lipid tails, in particular, are relevant for diffusion of membrane constituents and small molecules in and across membranes, and for structure and formation of membrane domains. We studied the effect of aspirin (acetylsalicylic acid, ASA) on local structure and dynamics of membranes composed of dimyristoylphosphocholine (DMPC) and cholesterol. Aspirin is a common analgesic, but is also used in the treatment of cholesterol. Using coherent inelastic neutron scattering experiments and molecular dynamics (MD) simulations, we present evidence that ASA binds to liquid- ordered, raft-like domains and disturbs domain organization and dampens collective fluctuations. By hydrogen-bonding to lipid molecules, ASA forms ‘superfluid’ complexes with lipid molecules that can organize laterally in superlattices and suppress cholesterol’s ordering effect. 1. Introduction Membrane research progresses with ever-increasing levels of granularity. Initial models of the membrane as an inert, physical barrier were revised with the discovery of membrane-embedded proteins. Singer & Nicholson [1] devised their famous ‘fluid mosaic’ model to describe a system where proteins float in a featureless soup of various lipid types. Most recently, membrane research has focused on membrane details on the level of individual lipids and proteins. The lipid environment in the specific region around a protein, such as the hydrophobic 2018 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.