Abstract
Cell membranes protect and compartmentalise cells and their organelles. The semi-permeable nature of these membranes controls the exchange of solutes across their structure. Characterising the interaction of small molecules with biological membranes is critical to understanding of physiological processes, drug action and permeation, and many biotechnological applications. This review provides an overview of how molecular simulations are used to study the interaction of small molecules with biological membranes, with a particular focus on the interactions of water, organic compounds, drugs and short peptides with models of plasma cell membrane and stratum corneum lipid bilayers. This review will not delve on other types of membranes which might have different composition and arrangement, such as thylakoid or mitochondrial membranes. The application of unbiased molecular dynamics simulations and enhanced sampling methods such as umbrella sampling, metadynamics and replica exchange are described using key examples. This review demonstrates how state-of-the-art molecular simulations have been used successfully to describe the mechanism of binding and permeation of small molecules with biological membranes, as well as associated changes to the structure and dynamics of these membranes. The review concludes with an outlook on future directions in this field.
Highlights
Biological membranes are semi-permeable structures present in all living organisms
molecular dynamics (MD) simulations can provide a wealth of information in atomistic detail on the interactions of small molecules with structural models of biological membranes
Unbiased MD simulations have provided insight into how SSMIs affect the structure and dynamics of lipid bilayers, which has assisted in rationalising experimental data on phase changes of membranes or understanding the molecular mechanism of cryoprotective agents and sugar molecules
Summary
Biological membranes are semi-permeable structures present in all living organisms. Membranes protect the cell from the external environment, compartmentalise cells and their organelles and control the selective transport of molecules in and out of these compartments. The fundamental concepts of model membranes, surface binding and permeation are introduced, followed by a brief summary of the experimental techniques most commonly used to study biological membranes and their interactions with small molecules. By controlling lipid composition and environmental factors, model membranes enable a more direct comparison of the surface binding or permeation of a set of small molecules with varying physicochemical properties. Seelig has described in detail the driving forces that govern the adsorption and insertion of peptides to membranes [55] Much of this theoretical framework is applicable to small molecules that do not penetrate into the bilayer (i.e. interactions that are restricted to surface binding). As for surface binding, permeation across a lipid bilayer is influenced by the physicochemical properties of the permeant molecule such as its molecular weight, shape, hydrophobicity/lipophilicity and net charge [58]. There is great interest in developing permeability models that can predict permeation by considering the physicochemical properties of the solute
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