One of the challenges in drug discovery and development is the low oral bioavailability of poorly permeable drugs such as peptides, proteins, and oligonucleotide molecules. One approach to enhance the absorption of poorly permeable drugs through the intestinal epithelium is coadministration with transient permeability enhancers (PEs). A number of formulations for oral peptide delivery based on transient PEs went into clinical trials. Among the most efficient transient PEs for poorly permeable molecules are the medium-chain fatty acids (MCFAs) such as sodium caprate, caprylate, and MCFA-based enhancers such as salcaprozate sodium (SNAC; a derivative of caprylate). MCFAs modulate the epithelial membranes in a mild, transient, and rapidly reversible way and are therefore ideal to use as transient PEs. They are natural constituents of food products such as milk, coconut oil, and dairy triglycerides, and their use as transient PEs has shown no significant toxicity effect, even on individuals receiving multiple doses. We have previously studied the interplay between PE molecules, the surrounding intestinal environment, and model lipid bilayers (see activity report). Now we want to continue, adding complexity with explicit peptide molecules as well. Methods: Peptide permeation will be studied with the Gromacs program for molecular dynamics (MD) simulations with umbrella sampling (US) or the accelerated weighted histogram (AWH) method and the solubility-diffusion model for calculation of permeability (P)-coefficients. Lipid bilayer systems of different compositions will represent cellular barriers of the small intestine. Accuracy and statistical errors will be estimated by bootstrap analysis. We will also continue to build computational fluid dynamics models of the small intestine (using comsol) looking at how different motility patterns affect the transport and absorption of (in particular) peptide-based drugs.