Proton Coupling and the Multiscale Kinetic Mechanism of a Peptide Transporter

ABSTRACTThe proton electrochemical gradient drives substrate transport across the cell membrane via a diverse set of secondary active transporters. Proton coupled peptide transporters (POTs) are important for peptide transport in prokaryotes and eukaryotic cells, where they mediate the uptake of di- and tri-peptides in addition to drug and pro-drug molecules. Previously, we captured a POT transporter from Staphylococcus hominis, PepTSh, in a cytoplasm-facing, inward open state (Minhas et al., 2018). Biochemical experiments have further revealed several critical residues for proton coupled transport; however, the precise role played by these residues in coupling proton binding to conformational changes as well as the timescales for proton transfers have remained obscure. Here, we employed multiscale modeling, including classical molecular dynamics, reactive molecular dynamics, and enhanced free energy sampling to characterize proton coupling within this transporter. We show directly that proton binding to a glutamate on TM7 opens the extracellular gate. The inward proton flow is found to induce movement of the peptide towards the cytosol by varying the protonation state of a second conserved glutamate on TM10. We also show that proton movement between TM7 and TM10 is thermodynamically driven and kinetically permissible, revealing a mechanism for proton movement inside the transporter.

Boron containing metal–organic framework for highly selective photocatalytic production of H2O2 by promoting two-electron O2 reduction

The adsorption sites of boron in UiO-66-B lead to in a larger amount of O2 adsorption; and the H+ is adsorbed on the oxygen adjacent to boron, which is more conducive to the proton coupling reaction of ˙O2− to H2O2 in the second step.

Continuous constant pH Molecular Dynamics Simulations of Transmembrane Proteins

Many membrane channels, transporters, and receptors utilize a pH gradient or proton coupling to drive functionally relevant conformational transitions. Conventional molecular dynamics simulations employ fixed protonation states, thus neglecting the coupling between protonation and conformational equilibria. Here we describe the membrane-enabled hybrid-solvent continuous constant pH molecular dynamics method for capturing atomic details of proton-coupled conformational dynamics of transmembrane proteins. Example protocols from our recent application studies of proton channels and ion/substrate transporters are discussed.

Allylic Proton-Proton Coupling in Stereodefined Alkylidenecyclobutanes and Alkylidenecycopentanes

Analysis of the 1H NMR spectra of eight stereodefined alkylidenecycloalkanes allows determination of the magnitude of allylic coupling in these compounds. In contrast to the trend normally observed, the magnitude of transoid-allylic coupling was found to be invariably greater by ~0.5 Hz than the cisoid-allylic coupling. The larger transoid-allylic coupling may be attributed to the slightly smaller dihedral angle relating allylic =C–C–H plane with the C=C–C plane in the E-isomers.

Bio-proton coupled semiconductor/metal-complex hybrid photoelectrocatalytic interface for efficient CO2 reduction

Aimed at high-efficiency biomimetic CO2 photoelectrochemical conversion, a bio-proton coupling metal-complex/semiconductor hybrid photoelectrocatalytic interface (Ru-BNAH/TiO2/Cu2O) was constructed by covalently modifying an in situ proton-transfer functionized molecular catalyst (Ru-BNAH) on the surface of a TiO2/Cu2O composite semiconductor substrate electrode.