Effect of Lipid Unsaturation on Membrane Protein Structure and Function from Multi-Microsecond Molecular Dynamics Simulations

Abstract

Lipid membrane composition is an important factor in controlling the structure and activity of many membrane proteins. This regulation can take place through the alteration of membrane physico-chemical properties or through direct protein-lipid interactions. Atomistic molecular dynamics simulations on the μs timescale can help uncover the general and specific mechanisms of protein function modulation. omega-3 lipids play key roles in controlling ion channel activity in the brain and heart, with deficiencies associated with a number of a number of health issues, including cardiac and Alzeimer's disease, cognitive function and vision disorders. We have explored the effects of lipid tail unsaturation by carrying out ∼10 μs simulations of well-characterized membrane proteins rhodopsin and ion channel KcsA, incorporated into lipid bilayers containing the sn-2 chain with 0 (palmitic), 1 (oleic) and 6 (docosahexaenoic, DHA) double bonds. We observed a marked preference for DHA to solvate the trans-membrane helices of the protein and have identified protein residues preferentially interacting with the unsaturated chains. We will report calculations that reveal the effects of lipid unsaturation on the protein structure and fluctuations, with implications for protein activity. Finally we will discuss ongoing simulations of the KcsA channel in both its closed and open (active) states, to directly uncover the role of lipid unsaturation in function.