Our research focuses on the Influenza-A M2 protein, a small homotetrameric, voltage-gated ion channel. Each monomer is 97 amino acids in length, and contains a single transmembrane (TM) domain of 19 residues. This channel is very effective in transporting protons and screens out other types of ions. Although no high resolution structural data for M2 are available to date, recent NMR and CD studies of this protein in phospholipid bilayers strongly suggest that the TM region is alpha-helical and has the quaternary structure of a 4-helix bundle. The mechanisms of channel gating by M2 is also currently unknown. There are two main hypotheses regarding gating of protons. One considers the formation of a water wire through the channel and the ability of such a structure to transfer protons through the channel. The second hypothesis is based on a proton shuttle mechanism mediated by four intraluminal histidine residues forming the gate.
Our aim i n this study has been to elucidate the gating mechanism of M2, and to demonstrate the stability of a structural model of M2 in an explicit water-phospholipid bilayer system. We have performed several molecular dynamics simulations, each consisting of a trajectory at least one nanosecond long. Each simulation corresponded to a different protonation state of the histidine residues in the gate. The unprotonated and single protonated forms involved in the proton shuttle mechanism were found to be stable over the full length of the trajectory. Furthermore, the orientation of water molecules inside the channel was conducive to effective proton transfer. In contrast, the form in which all four histidine residues are protonated, required in the water-wire mechanism, was unstable and disassociated on a timescale of 400 - 700 ps. Our results demonstrate that proton shuttle involving histidine residues of the protein is the most likely mechanism of proton transport in the M2 channel.
|Kozak, John J; Gray, Harry B; Garza-López, Roberto A (2018) Relaxation of structural constraints during Amicyanin unfolding. J Inorg Biochem 179:135-145|
|Alamo, Lorenzo; Pinto, Antonio; Sulbarán, Guidenn et al. (2018) Lessons from a tarantula: new insights into myosin interacting-heads motif evolution and its implications on disease. Biophys Rev 10:1465-1477|
|Viswanath, Shruthi; Chemmama, Ilan E; Cimermancic, Peter et al. (2017) Assessing Exhaustiveness of Stochastic Sampling for Integrative Modeling of Macromolecular Structures. Biophys J 113:2344-2353|
|Chu, Shidong; Zhou, Guangyan; Gochin, Miriam (2017) Evaluation of ligand-based NMR screening methods to characterize small molecule binding to HIV-1 glycoprotein-41. Org Biomol Chem 15:5210-5219|
|Portioli, Corinne; Bovi, Michele; Benati, Donatella et al. (2017) Novel functionalization strategies of polymeric nanoparticles as carriers for brain medications. J Biomed Mater Res A 105:847-858|
|Alamo, Lorenzo; Koubassova, Natalia; Pinto, Antonio et al. (2017) Lessons from a tarantula: new insights into muscle thick filament and myosin interacting-heads motif structure and function. Biophys Rev 9:461-480|
|Nguyen, Hai Dang; Yadav, Tribhuwan; Giri, Sumanprava et al. (2017) Functions of Replication Protein A as a Sensor of R Loops and a Regulator of RNaseH1. Mol Cell 65:832-847.e4|
|Sofiyev, Vladimir; Kaur, Hardeep; Snyder, Beth A et al. (2017) Enhanced potency of bivalent small molecule gp41 inhibitors. Bioorg Med Chem 25:408-420|
|Sato, Daisuke; Shannon, Thomas R; Bers, Donald M (2016) Sarcoplasmic Reticulum Structure and Functional Properties that Promote Long-Lasting Calcium Sparks. Biophys J 110:382-390|
|Towse, Clare-Louise; Rysavy, Steven J; Vulovic, Ivan M et al. (2016) New Dynamic Rotamer Libraries: Data-Driven Analysis of Side-Chain Conformational Propensities. Structure 24:187-199|
Showing the most recent 10 out of 508 publications