Elucidating the Molecular Basis of pH Activation of an Engineered Mechanosensitive Channel

Abstract

Mechanosensitive (MS) channels detect and respond to changes in the pressure profile of cellular membranes and transduce the mechanical energy into electrical and/or chemical signals. By re-engineering, however, the activation of some MS channels can be triggered by chemical signals such as pH change. Here, for the first time, we have elucidated, at an atomic level, the activation mechanism of an engineered MscL channel in response to the pH changes of the environment through a combination of equilibrium and non-equilibrium molecular dynamics (MD) simulations. The key highlights of our proposed activation mechanism are that: (1) periplasmic loops play a key role in activation, (2) loss of various hydrogen bonding and salt bridge interactions in the engineered MscL channel causes the opening of the channel, and (3) the most significant interactions lost during the activation process are those between the transmembrane (TM) helices 1 and 2 (TM1 and TM2). The orientation-based method in this work for generating and optimizing an open model of engineered MscL is a promising method for generating unknown states of proteins and for studying the activation processes in ion channels. This work facilitates the studies aimed at designing pH-triggered drug delivery liposomes (DDL), which embed MscL as a nanovalve.

Mechanistic Picture for Chemomechanical Coupling in a Bacterial Proton-Coupled Oligopeptide Transporter from Streptococcus Thermophilus

“…Further, to assess the conformational landscape of the 12 systems, we employed PCA analysis. , The impact of protonation/deprotonation on the protein conformation was clearly observed in the PCA analysis. When all 12 structures were projected onto a PC space built based on all trajectories, PC1 clearly differentiated the systems into two distinguished clusters (Figure A).…”

An investigation of the YidC-mediated membrane insertion of Pf3 coat protein using molecular dynamics simulations

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An Investigation of the YidC-Mediated Membrane Insertion of Pf3 Coat Protein Using Molecular Dynamics Simulations

“…The combination of equilibrium and non-equilibrium MD simulations has proven effective for investigating biological challenges. 12,[56][57][58][59][60][61][62][63][64] In this work, the YidC independent insertion mechanism was studied using non-equilibrium targeted MD (TMD) as implemented within the colvars module of NAMD. 65 TMD simulation was performed on the final conformation of the pose 1 system obtained from the 550 ns equilibrium trajectory in order to transfer the Pf3 peptide to the periplasmic side of the membrane, as seen in pose 2.…”