ABI innovation: Computational method for exploring the mysteries of cell-penetrating peptides

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This project aims to develop a new computational method and a web server for prediction of the cell-penetrating ability of naturally-occurring and synthetic peptides and analysis of their interactions with cellular membranes. Cell-penetrating peptides (CPPs) were discovered two decades ago and since then were used for delivery of various macromolecules into cells and tissues. However, the molecular mechanisms of passage of peptides through cell membranes still remain a mystery. To shed light on the mechanisms of direct membrane crossing by CPPs, an innovative theoretical method will be developed. This method will quantify the energetics of the processes underlying peptide entry into cells, including binding of peptides to membranes, their folding into alpha-helical and beta-sheet structures, and crossing the lipid bilayer by diffusion or by inducing membrane deformations, such as thinning, curving, or pore formation. The project is expected to have a significant scientific impact by providing unique methodology and the first public web server for discovery and design of novel CPPs. This method will be also valuable for analysis of interactions with membranes of a much wider spectrum of biologically active peptides and proteins with potentially beneficial or harmful physiological effects. The development and application of such general tool will advance scientific knowledge in the field of membrane peptides and proteins. An easy-to-use web tool will benefit a broad community of students, teachers and researchers engaged in the fields of biophysics, molecular and cell biology, bio-nanotechnology, and drug design. The project includes participation of students from the University of Michigan in development of the computational resources, as well as teaching K-12 students from socio-economically disadvantaged groups using videos, images, and tangible molecular models of peptides and proteins in membranes.The new method will combine a thermodynamic model of secondary structure formation by peptides and an anisotropic solvent model of the lipid bilayer that accounts for specific polarity profiles, curvature, elastic moduli, and transmembrane potential in different biological membranes. The proposed methodology will be extensively tested and implemented on a public web server that will allow the following: (1) to quantify membrane-peptide interactions, energy and binding modes, including deformations of the lipid bilayer by peptides (PPM 3.0); (2) to perform modeling of membrane-bound beta-sheets and alpha-helices, including generation and optimization of their all-atom three-dimensional structures (FMAP 2.0); and (3) to predict potential CPPs by calculating and evaluating their possible translocation mechanisms, pathways and energy barriers in the lipid bilayer (CPPpred). The CPPpred server will generate all-atom three-dimensional structures of peptides, estimate their membrane binding modes and energy barriers along the translocation pathway, and evaluate mechanisms of peptide translocation using their amino acid sequence and parameters of specific membranes as input. The high computational efficiency of the method will allow its application for large-scale computational screening of peptide databases to identify potential CPPs.