Molecular Dynamics Investigations Suggest a Non-specific Recognition Strategy of 14-3-3σ Protein by Tweezer: Implication for the Inhibition Mechanism.

Mingsong Shi,Dingguo Xu

doi:10.3389/fchem.2019.00237

Abstract

The supramolecular complex formed between protein and designed molecule has become one of the most efficient ways to modify protein functions. As one of the more well-studied model systems, 14-3-3 family proteins play an important role in regulating intracellular signaling pathways via protein-protein interactions. In this work, we selected 14-3-3σ as the target protein. Molecular dynamics simulations and binding free energy calculations were applied to identify the possible binding sites and understand its recognition ability of the supramolecular inhibitor, the tweezer molecule (CLR01). On the basis of our simulation, major interactions between lysine residues and CLR01 come from the van der Waals interactions between the long alkyl chain of lysine and the cavity formed by the norbornadiene and benzene rings of the inhibitor. Apart from K214, which was found to be crystallized with this inhibitor, other lysine sites have also shown their abilities to form inclusion complexes with the inhibitor. Such non-specific recognition features of CLR01 against 14-3-3σ can be used in the modification of protein functions via supramolecular chemistry.

Highlights

The intriguing strategies using supramolecular chemistry in the modification of protein functions via host-guest interactions have attracted extensive interests
Surface exposed charged residues like lysine and arginine are usually used as the target recognition sites, which can form the supramolecular complexes with macrocycles, e.g., cyclo[6]aramide (Pan et al, 2018), p-sulfonatocalix[4]arene (Thomas and Ward, 2005; Perret et al, 2006), crown ethers (Shimojo et al, 2006) and cyclodextrins (Kano and Ishida, 2007)
As we have mentioned above, there are total of 17 lysine residues located on the surface of 14-3-3σ

Summary

Introduction

The intriguing strategies using supramolecular chemistry in the modification of protein functions via host-guest interactions have attracted extensive interests. More than one thousand binding partner proteins of the 14-3-3 domain have been identified including transcription factors, signaling molecules, tumor suppressors, biosynthetic enzymes, cell cycle regulation, cell proliferation, protein trafficking, metabolic regulation, and apoptosis (Fu et al, 2000; Aitken, 2006; Hermeking, 2006) They show no enzymatic activity by themselves, 14-3-3 proteins can alter the conformation, localization, stability, phosphorylation state as well as activity of a target protein via PPIs (Muslin and Xing, 2000; Tzivion et al, 2001; Aitken, 2006; Aghazadeh and Papadopoulos, 2016). Their interaction is often considered to be one of the most ideal models for understanding PPIs

Results

Discussion

Conclusion