Chapter 5 - In silico approaches for lipids: Interactions of membrane-active agents with lipids

Abstract

Plasma membrane effects of membrane-active agents (MAAs), such as antimicrobial peptides (AMPs), chemotherapy drugs (CDs), aptamers, etc. are demonstrated using theoretical techniques including modeling, in silico numerical computations (NCs), molecular dynamic (MD) simulations, etc. We have recently developed a direct detection method (DDM) (US patented) to demonstrate the application of these techniques in addressing the MAAs’ statistical interactions with membrane systems. The MAAs are often found to interact with membrane ingredients, especially with various lipids, and thus get adsorbed inside lipid bilayer following specific molecular mechanism explained using valid theoretical formalisms. Such physical adsorption of MAAs leads to creation of membrane-disrupting structures including especially various types of ion channels. In vitro experimental techniques covered in our DDM, such as fluorescence imaging, electrophysiology records of membrane currents, etc., can help demonstrate the membrane effects of MAAs in constructed planar bilayer or liposome systems. Both in silico and in vitro techniques produce data that mutually complement each other and thus help us establish proof of principles behind MAAs’ membrane actions due to agents’ direct or indirect membrane adsorption and/or lipid interactions. In this chapter, we shall explore at least three case studies involving membrane effects of sets of AMPs (e.g., gramicidin A and alamethicin), CDs (colchicine and taxol), and aptamers (short DNA nucleotide sequences). Due to the nature of the chapter, we shall focus especially at their molecular level interactions with target lipids, detect the underlying mechanisms, and understand their binding phenomena using in silico studies. This analysis will be helpful in understanding MAAs’ physicochemical properties, their physical membrane availability, and thus aid in designing novel compounds as MAAs that might be found useful as drugs for various diseases originated at or linked to plasma membrane structures and functions.