Kusaka, A. | Search bioRxiv

bioRxiv2020

Molecular interaction mechanism of 14-3-3ε protein with phosphorylated Myeloid leukemia factor 1 revealed by an enhanced conformational sampling

Enhanced conformational sampling, a genetic-algorithm-guided multi-dimensional virtual-system coupled molecular dynamics, can provide equilibrated conformational distributions of a receptor protein and a flexible ligand at room temperature. The distributions provide not only the most stable but also semi-stable complex structures, and propose a ligand-receptor binding process. This method was applied to a system consisting of a receptor protein, 14-3-3{varepsilon}, and a flexible peptide, phosphorylated Myeloid leukemia factor 1 (pMLF1). The results present comprehensive binding pathways of pMLF1 to 14-3-3{varepsilon}. We identified four thermodynamically stable clusters of MLF1 on the 14-3-3{varepsilon} surface, and free-energy barriers among some clusters. The most stable cluster includes two high-density spots connected by a narrow corridor. When pMLF1 passes the corridor, a salt-bridge relay (switching) related to the phosphorylated residue of pMLF1 occurs. Conformations in one high-density spots are similar to the experimentally determined complex structure. Three-dimensional distributions of residues in the intermolecular interface rationally explain the binding-constant changes resultant from alanine-mutation experiment for the residues. We performed a simulation of non-phosphorylated peptide and 14-3-3{varepsilon}, which demonstrated that the complex structure was unstable, suggesting that phosphorylation of the peptide is crucially important for binding to 14-3-3{varepsilon}.

biophysics↗

bioRxiv2019

Hydrogen Bond Donors and Acceptors are Generally Depolarizedin α-Helices as Revealed by a Molecular Tailoring Approach

Hydrogen-bond (H-bond) interaction energies in -helices of short alanine peptides were systematically examined by precise DFT calculations, followed by a molecular tailoring approach (MTA). The contribution of each H-bond interaction in -helices was estimated in detail from the entire conformation energies, and the results were compared with those in the minimal H-bond models, in which only H-bond donors and acceptors exist with the capping methyl groups. Consequently, the former interaction energies were always significantly weaker than the latter energies, when the same geometries of the H-bond donors and acceptors were applied. The chemical origin of this phenomenon was investigated by analyzing the differences among the electronic structures of the local peptide backbones of the -helices and those of the minimal H-bond models. Consequently, we found that the reduced H-bond energy originated from the depolarizations of both the H-bond donor and acceptor groups, due to the repulsive interactions with the neighboring polar peptide groups in the -helix backbone. The classical force-fields provide similar H-bond energies to those in the minimal H-bond models, which ignore the current depolarization effect, and thus they overestimate the actual H-bond energies in -helices.

biophysics↗