Computer Simulations of Antimicrobial Tripeptides with Proteolytic Stability Towards Chymotrypsin

Abstract

The emerging crisis of antimicrobial resistance calls for the development of new therapeutic drugs. Antimicrobial peptides (AMPs), found in a variety of species as part of the host-defence mechanisms, serves as promising candidates for clinical use. Studies of well-known AMPs like lactoferrin have lead to the preparation of short cationic AMPs (CAPs) with broad spectrum antimicrobial activity against bacteria, fungi, enveloped viruses, parasites and cancer cells. However, in order for the CAPs to have therapeutic effect it must face and overcome several \textit{in vivo} challenges. One major hurdle is the proteolytic stability towards chymotrypsin, an enzyme present in the gastrointestinal tract. In this study, the interaction between chymotrypsin and active CAPs has been studied using molecular modelling and computer simulations. It was found that CAPs cleaved by the enzyme have stronger electrostatic interactions with the enzyme than the stable CAPs, both in the bound state and in the transition state. The stable CAPs were found to have structural features which can hinder optimal orientation of the main-chain in the transition state, and therefore lower the electrostatic stabilization. Furthermore, the enzyme was found to be preorganized with a polar environment that stabilizes the transition state more than the reactant state.