Comparative Study Of Biologically Contextual Effects On Peptide-Mediated Protein Interactions At Structural,energetic And Dynamic

Since the end of the 20 th century,drug development has attracted an accumulated interest in the drug design community.This is an interdisciplinary subject across a variety of areas such as pharmacy,chemistry,structural biology and computer science.A large number of potential drug targets have been identified over the past decades,such as enzymes,receptors,and ion channels,and on this basis,one can rationally design drug molecules regarding the chemically structural features of cognate ligands and natural substrates to derive lead molecular entities,this is current focus of new drug developmentIt is well known that the protein–protein interactions(PPIs)regulate a variety of cellular functions,including cell cycle progression,signal transduction,and metabolic pathways.Many important PPIs,particularly those that are transient,low-affinity or related to post-translational modification events like phosphorylation,are mediated by the binding of a globular domain in one protein to a short peptide segment in another;such peptide-mediated interactions(PMIs)could explain up to 15–40% of the cellular interactome.Previous,considering that only the peptide segment directly participates in PMIs,researchers commonly use protein–peptide system to represent a complete PPI,where the peptide segment is stripped from its parent protein.However,it is believed that this stripped segment cannot fully recover the PPI due to the large flexibility and intrinsic disorder of isolated peptide in solvent,and the additional contributions such as conformational constraint and scaffold effect should be addressed on the peptide in protein context.Here,we perform a proof-of-concept study at structural,energetic and dynamic levels to explore whether the stripped protein–peptide system can mimic its intact parent PPI and what is the difference between them.In addition,a case study is perform on the proto-oncogene non-receptor tyrosine kinase,Src,which contains two PMIs termed as self-binding peptides(SBPs)that bind separately to SH3 and SH2 domains of the kinase.State-of-the-art molecular dynamics simulations and post binding energetics analysis reveal that disrupting the kinase-intramolecular interactions of SH3 and SH2 domains with their cognate SBP ligands can result in totally different effects on the structural dynamics of Src kinase architecture,demonstrating that molecular targeting of the SBPbased PMIs can be used as a new strategy to regulate kinase activity and function.