In Silico Prediction of the Binding, Folding, Insertion, and Overall Stability of Membrane-Active Peptides

Membrane-active peptides (MAPs) are short-length peptides used for potential biomedical applications in diagnostic imaging of tissues, targeted drug delivery, gene delivery, and antimicrobials and antibiotics. The broad appeal of MAPs is that they are infinitely variable, relatively low cost, and biocompatible. However, experimentally characterizing the specific properties of a MAP or its many variants is a low-resolution and potentially time-consuming endeavor; molecular dynamics (MD) simulations have emerged as an invaluable tool in identifying the biophysical interactions that are fundamental to the function of MAPs. In this chapter, a step-by-step approach to discreetly model the binding, folding, and insertion of a membrane-active peptide to a model lipid bilayer using MD simulations is described. Detailed discussion is devoted to the critical aspects of running these types of simulations: prior knowledge of the system, understanding the strengths and weaknesses of molecular mechanics force fields, proper construction and equilibration of the system, realistically estimating both experimental and computational timescales, and leveraging analysis to make direct comparisons to experimental results as often as possible.