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 type 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.

Toll-like receptors (TLRs) are widely expressed pattern recognition receptors that bind to conserved molecular patterns expressed by pathogens and damaged cells. After recognition, activated TLRs induce the expression of various proinflammatory and antiviral molecules. Thus, TLRs are potential targets for treatment strategies aimed at boosting the adaptive immune response to vaccines, controlling infections, enhancing immune responses during tumor treatment and attenuating immune responses in inflammatory disorders. This Special Report examines the potential of TLRs as targets for the treatment of cancer, infections and inflammatory diseases. Here, we make a particular emphasis on molecules capable of modulating TLRs and their therapeutic applications.

T-cell epitopes are specific peptide sequences derived from foreign or own proteins that can initiate an immune response and which are recognized by specific T-cells when displayed on the surface of other cells. The prediction of T-cell epitopes is of particular interest in vaccine design, disease prevention and the development of immunotherapeutics. There are two principal categories of predictive methods: peptide-sequence based and peptide-structure-based. Sequence-based methods make use of various approaches to identify likely immunogenic amino acid sequences, such as sequence motifs, decision trees, partial least squares (PLS), quantitative matrices (QM), artificial neural networks (ANN), hidden Markov models (HMM), and support vector machines (SVM).Structure-based methods are more diverse in nature and involve approaches such as quantitative structure-activity relationships (QSAR), molecular modelling, molecular docking and molecular dynamics simulations (MD). This review highlights the key features of all of these approaches, provides some key examples of their application, and compares and contrasts the most important methods currently in use.

The barrier imposed by the outer layer of the skin, the stratum corneum, creates an almost impermeable environment for exogenous substances. Few lipophilic drugs with low molecular mass can passively diffuse through this layer, highlighting the need to develop methods to enable the delivery of more drugs via the transdermal route. The prodrug approach involves modifying the structure of a drug molecule to enhance its permeability across the skin, but it is often difficult to predict how exactly changes in chemical structure affect permeation. This study uses molecular dynamics simulations to predict permeability values and adequately characterise the molecular mechanism of permeation of the prodrugs Me-5ALA and its parent compound 5ALA across a molecular model of the lipid bilayers of the human stratum corneum. The influence of increased hydrophobicity in Me-5ALA on its permeation revealed a reduction in hydrogen bonding capability that enables it to interact more favourably with the hydrophobic region of the bilayer and diffuse at a faster rate with less resistance, thus making it a better permeant compared to its more hydrophilic parent compound. This molecular simulation approach offers a promising route for the rational design of drug molecules that can permeate effectively across the stratum corneum.