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Biochimica et Biophysica Acta  2011;1818(4):942-950.
Changes in inter-helical hydrogen bonding are associated with the conformational dynamics of membrane proteins. The function of the protein depends on the surrounding lipid membrane. Here we review through specific examples how dynamical hydrogen bonds can ensure an elegant and efficient mechanism of long-distance intra-protein and protein-lipid coupling, contributing to the stability of discrete protein conformational substates and to rapid propagation of structural perturbations.
PMCID: PMC3288666  PMID: 22178866
membrane protein structure; hydrogen bond; membrane protein dynamics; lipid-protein interactions
2.  Ser/Thr Motifs in Transmembrane Proteins: Conservation Patterns and Effects on Local Protein Structure and Dynamics 
The Journal of membrane biology  2012;245(11):717-730.
We combined systematic bioinformatics analyses and molecular dynamics simulations to assess the conservation patterns of Ser and Thr motifs in membrane proteins, and the effect of such motifs on the structure and dynamics of α-helical transmembrane (TM) segments. We find that Ser/Thr motifs are often present in β-barrel TM proteins. At least one Ser/Thr motif is present in almost half of the sequences of α-helical proteins analyzed here. The extensive bioinformatics analyses and inspection of protein structures led to the identification of molecular transporters with noticeable numbers of Ser/Thr motifs within the TM region. Given the energetic penalty for burying multiple Ser/Thr groups in the membrane hydrophobic core, the observation of transporters with multiple membrane-embedded Ser/Thr is intriguing and raises the question of how the presence of multiple Ser/Thr affects protein local structure and dynamics. Molecular dynamics simulations of four different Ser-containing model TM peptides indicate that backbone hydrogen bonding of membrane-buried Ser/Thr hydroxyl groups can significantly change the local structure and dynamics of the helix. Ser groups located close to the membrane interface can hydrogen bond to solvent water instead of protein backbone, leading to an enhanced local solvation of the peptide.
PMCID: PMC3910433  PMID: 22836667
Bioinformatics; Molecular dynamics; Molecular transporters and receptors; Ser/Thr motifs; Transmembrane proteins
3.  Exploring cavity dynamics in biomolecular systems 
BMC Bioinformatics  2013;14(Suppl 19):S5.
The internal cavities of proteins are dynamic structures and their dynamics may be associated with conformational changes which are required for the functioning of the protein. In order to study the dynamics of these internal protein cavities, appropriate tools are required that allow rapid identification of the cavities as well as assessment of their time-dependent structures.
In this paper, we present such a tool and give results that illustrate the applicability for the analysis of molecular dynamics trajectories. Our algorithm consists of a pre-processing step where the structure of the cavity is computed from the Voronoi diagram of the van der Waals spheres based on coordinate sets from the molecular dynamics trajectory. The pre-processing step is followed by an interactive stage, where the user can compute, select and visualize the dynamic cavities. Importantly, the tool we discuss here allows the user to analyze the time-dependent changes of the components of the cavity structure. An overview of the cavity dynamics is derived by rendering the dynamic cavities in a single image that gives the cavity surface colored according to its time-dependent dynamics.
The Voronoi-based approach used here enables the user to perform accurate computations of the geometry of the internal cavities in biomolecules. For the first time, it is possible to compute dynamic molecular paths that have a user-defined minimum constriction size. To illustrate the usefulness of the tool for understanding protein dynamics, we probe the dynamic structure of internal cavities in the bacteriorhodopsin proton pump.
PMCID: PMC3980386  PMID: 24564434
Structure (London, England : 1993)  2012;20(11):1893-1904.
Lactose permease of Escherichia coli (LacY) catalyzes symport of a galactopyranoside and an H+ via an alternating access mechanism. The transition from an inward- to an outward-facing conformation of LacY involves sugar-release followed by deprotonation. Because the transition depends intimately upon the dynamics of LacY in a bilayer environment, molecular dynamics (MD) simulations may be the only means of following the accompanying structural changes in atomic detail. We describe here MD simulations of wild-type apo LacY in phosphatidylethanolamine (POPE) lipids that features two protonation states of the critical Glu325. While the protonated system displays configurational stability, deprotonation of Glu325 causes significant structural rearrangements that bring into proximity sidechains important for H+ translocation and sugar binding and closes the internal cavity. Moreover, protonated LacY in phosphatidylcholine (DMPC) lipids shows that the observed dynamics are lipid-dependent. Together, the simulations describe early dynamics of the inward-to-outward transition of LacY that agree well with experimental data.
PMCID: PMC3496080  PMID: 23000385
lactose permease; protonation states; protein-lipid interactions; MD simulations
5.  Role of Arg82 in the early steps of the bacteriorhodopsin proton-pumping cycle 
The journal of physical chemistry. B  2011;115(21):7129-7135.
Proton transfer reactions in the bacteriorhodopsin light-driven proton pump are coupled with structural rearrangements of protein amino acids and internal water molecules. It is generally thought that the first proton transfer step from retinal Schiff base to the nearby Asp85 is coupled with movement of the Arg82 sidechain away from Asp85 and towards the extracellular proton release group. This movement of Arg82 likely triggers the release of the proton from the proton release group to the extracellular bulk. The exact timing of the movement of Arg82, and how this movement is coupled with proton transfer is still not understood in molecular detail. Here, we address these questions by computing the free energy for the movement of the Arg82 side chain. The calculations indicate that protonation of Asp85 leads to a fast reorientation of the Arg82 side chain towards the extracellular proton release group.
PMCID: PMC3135100  PMID: 21561116
6.  Dynamics of SecY Translocons with Translocation-Defective Mutations 
The SecY/Sec61 translocon complex, located in the endoplasmic reticulum membrane of eukaryotes (Sec61) or the plasma membrane of prokaryotes (SecY), mediates the transmembrane secretion or insertion of nascent proteins. Mutations that permit the secretion of nascent proteins with defective signal sequences (Prl-phenotype), or interfere with the transmembrane orientation of newly synthesized protein segments, can affect protein topogenesis. The crystallographic structure of SecYEβ from Methanococcus jannaschii revealed widespread distribution of mutations causing topogenesis defects, but not their molecular mechanisms. Based upon prolonged molecular dynamics simulations of wild-type M. jannaschii SecYEβ and an extensive sequence-conservation analysis, we show that the closed-state of the translocon is stabilized by hydrogen-bonding interactions of numerous highly conserved amino acids. Perturbations induced by mutation at various locations are rapidly relayed to the plug segment that seals the wild-type closed-state translocon, leading to displacement and increased hydration of the plug.
PMCID: PMC2909450  PMID: 20637421
protein biosynthesis; SecY/Sec61 translocon; hydrogen bonding; molecular dynamics simulations
7.  Festschrift in the Honor of Stephen H. White’s 70th Birthday 
The Journal of Membrane Biology  2010;239(1-2):1-3.
The Symposium ‘Frontiers in membrane and membrane protein biophysics: experiments and theory’, held this year at the University of California, Irvine (August 19–20), celebrated the 70th Birthday of Stephen H. White by bringing together distinguished experimentalists and theoreticians to discuss the state of the art and future challenges in the field of membrane and membrane protein biophysics. The meeting and this special issue highlight the highly interdisciplinary nature of membrane and membrane protein biophysics, and the tremendous contributions that S. H. White and his lab have brought to the field.
PMCID: PMC3030939  PMID: 21191785
S. H. White; Membrane and membrane protein biophysics
8.  Long-distance proton transfer with a break in the bacteriorhodopsin active site 
Bacteriorhodopsin is a proton-pumping membrane protein found in the plasma membrane of the archaeon Halobacterium salinarium. Light-induced isomerization of the retinal chromophore from all-trans to 13-cis leads to a sequence of five conformation-coupled proton transfer steps and the net transport of one proton from the cytoplasmic to the extracellular side of the membrane. The mechanism of the long-distance proton transfer from the primary acceptor Asp85 to the extracellular proton release group during the O→bR is poorly understood. Experiments suggest that this long-distance transfer could involve a transient state [O] in which the proton resides on the intermediate carrier Asp212.1 To assess whether the transient protonation of Asp212 participates in the deprotonation of Asp85, we performed hybrid Quantum Mechanics/Molecular Mechanics proton transfer calculations using different protein structures, and with different retinal geometries and active site water molecules. The structural models were assessed by computing UV-Vis excitation energies and C=O vibrational frequencies. The results indicate that a transient [O] conformer with protonated Asp212 could indeed be sampled during the long-distance proton transfer to the proton release group. Our calculations suggest that in the starting proton transfer state O, the retinal is strongly twisted, and at least three water molecules are present in the active site.
PMCID: PMC2746972  PMID: 19405533
9.  Rhomboid protease dynamics and lipid interactions 
Intramembrane proteases, which cleave TM helices, participate in numerous biological processes encompassing all branches of life. Several crystallographic structures of Escherichia coli GlpG rhomboid protease have been determined. In order to understand GlpG dynamics and lipid interactions in a native-like environment, we have examined the molecular dynamics of wild-type and mutant GlpG in different membrane environments. The irregular shape and small hydrophobic thickness of the protein cause significant bilayer deformations that may be important for substrate entry into the active site. Hydrogen-bond interactions with lipids are paramount in protein orientation and dynamics. Mutations in the unusual L1 loop cause changes in protein dynamics and protein orientation that are relayed to the His-Ser catalytic dyad. Similarly, mutations in TM5 change the dynamics and structure of the L1 loop. These results imply that the L1 loop has an important regulatory role in proteolysis.
PMCID: PMC2679947  PMID: 19278654
lipid bilayers; lipid-protein interactions; intramembrane protease; molecular dynamics simulations; phosphatidylcholine; phosphatidylethanolamine
10.  Structure, dynamics and reactions of protein hydration water. 
The apparent simplicity of the water molecule belies the wide range of fascinating protein phenomena in which it participates. We review recent computer simulation work on buried, internal water molecules, discussing the thermodynamics of water molecule binding and the participation of water in proton transfer reactions. Surface water molecules are also considered, with emphasis on the modification of average solvent structure on a protein surface, the role of water in the protein dynamical 'glass' transition and a simplified description of the protein motions thereby activated.
PMCID: PMC1693407  PMID: 15306375

Results 1-10 (10)