Research and Development

@article{Wang2015,

title = {Pyridoxamine is a substrate of the energy-coupling factor transporter HmpT},

author = {Tingliang Wang and Armando J. de Jesus and Yigong Shi and Hang Yin},

url = {https://www.nature.com/articles/celldisc201514},

doi = {10.1038/celldisc.2015.14},

year  = {2015},

date = {2015-07-14},

journal = {Cell Discovery},

volume = {1},

pages = {15014},

abstract = {Energy-coupling factor (ECF) transporters belong to a novel family of proteins that forms a subset within the ATP-binding cassette (ABC) transporter family. These proteins are responsible for the uptake of micronutrients in bacteria. ECF transporters are composed of four proteins: the A- and A′-components, the T-component and the S-component. One of the ECF transporters, named HmpT, was crystallized in the apo form with all four components. It is currently unknown whether HmpT serves as a transporter for hydroxymethyl pyrimidine or the different forms of vitamin B6 (pyridoxine, pyridoxal or pyridoxamine). Using a combination of molecular dynamics (MD) simulations and mass spectrometry, we have identified pyridoxamine to be the preferred substrate of HmpT. Mass spectra show that the mass of the substrate from the HmpT–substrate complex matches that of pyridoxamine. MD simulations likewise indicate that pyridoxamine interacts most strongly with most of the conserved residues of the S-component (Glu 41, His 84 and Gln 43) compared with the other vitamin B6 forms. Furthermore, the simulations have implied that loops 1 and 5 of the S-component can participate in the gating action for HmpT.},

keywords = {ECF transporters, gating mechanism, HmpT, mass spectrometry, molecular dynamics, S-component},

pubstate = {published},

tppubtype = {article}

}

@article{deJesus2012,

title = {The determinants of hydrophobic mismatch response for transmembrane helices},

author = {Armando J. de Jesus and Toby W. Allen},

url = {https://www.sciencedirect.com/science/article/pii/S0005273612003252},

doi = {10.1016/j.bbamem.2012.09.012},

year  = {2012},

date = {2012-09-17},

journal = {Biochimica et Biophysica Acta (BBA) - Biomembranes},

volume = {1828},

number = {2},

pages = {851-863},

abstract = {Hydrophobic mismatch arises from a difference in the hydrophobic thickness of a lipid membrane and a transmembrane protein segment, and is thought to play an important role in the folding, stability and function of membrane proteins. We have investigated the possible adaptations that lipid bilayers and transmembrane α-helices undergo in response to mismatch, using fully-atomistic molecular dynamics simulations totaling 1.4 μs. We have created 25 different tryptophan-alanine-leucine transmembrane α-helical peptide systems, each composed of a hydrophobic alanine–leucine stretch, flanked by 1–4 tryptophan side chains, as well as the β-helical peptide dimer, gramicidin A. Membrane responses to mismatch include changes in local bilayer thickness and lipid order, varying systematically with peptide length. Adding more flanking tryptophan side chains led to an increase in bilayer thinning for negatively mismatched peptides, though it was also associated with a spreading of the bilayer interface. Peptide tilting, bending and stretching were systematic, with tilting dominating the responses, with values of up to ~ 45° for the most positively mismatched peptides. Peptide responses were modulated by the number of tryptophan side chains due to their anchoring roles and distributions around the helices. Potential of mean force calculations for local membrane thickness changes, helix tilting, bending and stretching revealed that membrane deformation is the least energetically costly of all mismatch responses, except for positively mismatched peptides where helix tilting also contributes substantially. This comparison of energetic driving forces of mismatch responses allows for deeper insight into protein stability and conformational changes in lipid membranes.},

keywords = {free energy, hydrophobic mismatch, membrane protein, molecular dynamics, protein–lipid interactions},

pubstate = {published},

tppubtype = {article}

}

@article{deJesus2012b,

title = {The role of tryptophan side chains in membrane protein anchoring and hydrophobic mismatch},

author = {Armando J. de Jesus and Toby W. Allen},

url = {https://www.sciencedirect.com/science/article/pii/S0005273612003227},

doi = {10.1016/j.bbamem.2012.09.009},

year  = {2012},

date = {2012-09-16},

journal = {Biochimica et Biophysica Acta (BBA) - Biomembranes},

volume = {1828},

number = {2},

pages = {864-876},

abstract = {Tryptophan (Trp) is abundant in membrane proteins, preferentially residing near the lipid–water interface where it is thought to play a significant anchoring role. Using a total of 3 μs of molecular dynamics simulations for a library of hydrophobic WALP-like peptides, a long poly-Leu α-helix, and the methyl-indole analog, we explore the thermodynamics of the Trp movement in membranes that governs the stability and orientation of transmembrane protein segments. We examine the dominant hydrogen-bonding interactions between the Trp and lipid carbonyl and phosphate moieties, cation–π interactions to lipid choline moieties, and elucidate the contributions to the thermodynamics that serve to localize the Trp, by ~ 4 kcal/mol, near the membrane glycerol backbone region. We show a striking similarity between the free energy to move an isolated Trp side chain to that found from a wide range of WALP peptides, suggesting that the location of this side chain is nearly independent of the host transmembrane segment. Our calculations provide quantitative measures that explain Trp's role as a modulator of responses to hydrophobic mismatch, providing a deeper understanding of how lipid composition may control a range of membrane active peptides and proteins.},

keywords = {free energy, hydrophobic mismatch, membrane protein, molecular dynamics, protein–lipid interactions, tryptophan},

pubstate = {published},

tppubtype = {article}

}