Schäfer, Lars V.

[["dc.bibliographiccitation.firstpage","6812"],["dc.bibliographiccitation.issue","21"],["dc.bibliographiccitation.journal","Journal of the American Chemical Society"],["dc.bibliographiccitation.lastpage","6819"],["dc.bibliographiccitation.volume","129"],["dc.contributor.author","Groenhof, Gerrit"],["dc.contributor.author","Schäfer, Lars V."],["dc.contributor.author","Boggio-Pasqua, Martial"],["dc.contributor.author","Goette, Maik"],["dc.contributor.author","Grubmüller, Helmut"],["dc.contributor.author","Robb, Michael A."],["dc.date.accessioned","2018-04-23T11:47:47Z"],["dc.date.available","2018-04-23T11:47:47Z"],["dc.date.issued","2007"],["dc.description.abstract","Multiconfigurational ab initio calculations and QM/MM molecular dynamics simulations of a photoexcited cytosine−guanine base pair in both gas phase and embedded in the DNA provide detailed structural and dynamical insights into the ultrafast radiationless deactivation mechanism. Photon absorption promotes transfer of a proton from the guanine to the cytosine. This proton transfer is followed by an efficient radiationless decay of the excited state via an extended conical intersection seam. The optimization of the conical intersection revealed that it has an unusual topology, in that there is only one degeneracy-lifting coordinate. This is the central mechanistic feature for the decay both in vacuo and in the DNA. Radiationless decay occurs along an extended hyperline nearly parallel to the proton-transfer coordinate, indicating the proton transfer itself is not directly responsible for the deactivation. The seam is displaced from the minimum energy proton-transfer path along a skeletal deformation of the bases. Decay can thus occur anywhere along the single proton-transfer coordinate, accounting for the remarkably short excited-state lifetime of the Watson−Crick base pair. In vacuo, decay occurs after a complete proton transfer, whereas in DNA, decay can also occur much earlier. The origin of this effect lies in the temporal electrostatic stabilization of dipole in the charge-transfer state in DNA."],["dc.identifier.doi","10.1021/ja069176c"],["dc.identifier.gro","3142268"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/13396"],["dc.language.iso","en"],["dc.notes.intern","lifescience updates Crossref Import"],["dc.notes.status","final"],["dc.relation.issn","0002-7863"],["dc.title","Ultrafast Deactivation of an Excited Cytosine−Guanine Base Pair in DNA"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.peerReviewed","no"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","530"],["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","Angewandte Chemie International Edition"],["dc.bibliographiccitation.lastpage","536"],["dc.bibliographiccitation.volume","46"],["dc.contributor.author","Schäfer, Lars V."],["dc.contributor.author","Groenhof, Gerrit"],["dc.contributor.author","Klingen, Astrid R."],["dc.contributor.author","Ullmann, G. Matthias"],["dc.contributor.author","Boggio-Pasqua, Martial"],["dc.contributor.author","Robb, Michael A."],["dc.contributor.author","Grubmüller, Helmut"],["dc.date.accessioned","2017-09-07T11:52:29Z"],["dc.date.available","2017-09-07T11:52:29Z"],["dc.date.issued","2007"],["dc.description.abstract","Molecular light‐switch: Off–on switching of the fluorescence of the protein asFP595 involves a trans–cis isomerization. Mixed quantum/classical simulations elucidate the spectroscopic properties of asFP595 and give detailed insights into the photoswitching mechanism. The conformational trans–cis switching triggers a proton‐transfer cascade between the chromophore and adjacent amino acids."],["dc.identifier.doi","10.1002/ange.200602315"],["dc.identifier.gro","3144945"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/2626"],["dc.language.iso","en"],["dc.notes.intern","Crossref Import"],["dc.notes.status","final"],["dc.publisher","Wiley-Blackwell"],["dc.relation.issn","1433-7851"],["dc.title","Photoswitching of the Fluorescent Protein asFP595: Mechanism, Proton Pathways, and Absorption Spectra"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.peerReviewed","no"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1693"],["dc.bibliographiccitation.issue","14"],["dc.bibliographiccitation.journal","J Comput Chem."],["dc.bibliographiccitation.lastpage","1702"],["dc.bibliographiccitation.volume","27"],["dc.contributor.author","Lange, Oliver F."],["dc.contributor.author","Schäfer, Lars V."],["dc.contributor.author","Grubmüller, Helmut"],["dc.date.accessioned","2018-04-29T09:45:23Z"],["dc.date.available","2018-04-29T09:45:23Z"],["dc.date.issued","2006"],["dc.description.abstract","The major bottleneck of today's atomistic molecular dynamics (MD) simulations is that because of the enormous computational effort involved, only processes at nanoseconds to microseconds time scales or faster can be studied directly. Unfortunately, apart from a few exceptions, relevant processes, such as chemical reactions or many large scale conformational transitions in proteins, occur at slower time scales and therefore are currently far out of reach for conventional MD. The flooding technique addresses this problem by inclusion of a flooding potential into the force field. This flooding potential locally destabilizes the educt state and thereby significantly accelerates the escape from the initial energy well without affecting the reaction pathway. Here, we summarize the theory and method for the computational chemistry community and detail the implementation within the official version 3.3 of the freely available MD program package GROMACS. Two examples shall demonstrate the application of flooding to accelerate conformational transitions and chemical reactions. The second example was carried out within a QM/MM framework."],["dc.identifier.doi","10.1002/jcc.20473"],["dc.identifier.gro","3142278"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/13780"],["dc.language.iso","en"],["dc.notes.intern","lifescience updates Crossref Import"],["dc.notes.status","final"],["dc.relation.issn","0192-8651"],["dc.title","Flooding in GROMACS: Accelerated Barrier Crossings in Molecular Dynamics"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.peerReviewed","no"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","3250"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","Journal of the American Chemical Society"],["dc.bibliographiccitation.lastpage","3251"],["dc.bibliographiccitation.volume","130"],["dc.contributor.author","Groenhof, Gerrit"],["dc.contributor.author","Schäfer, Lars V."],["dc.contributor.author","Boggio-Pasqua, Martial"],["dc.contributor.author","Grubmüller, Helmut"],["dc.contributor.author","Robb, Michael A."],["dc.date.accessioned","2018-02-13T12:55:37Z"],["dc.date.available","2018-02-13T12:55:37Z"],["dc.date.issued","2008-03-19"],["dc.description.abstract","We have performed excited-state dynamics simulations of the Arg52Gln (R52Q) mutant of photoactive yellow protein (PYP). The results of these simulations demonstrate that in the mutant the primary events after photoexcitation are different from those in the wild-type. In the mutant, the chromophore predominantly undergoes single bond photoisomerization, whereas in the wild-type, photoisomerization of the double bond occurs. Furthermore, the excited-state lifetime is around three times longer than in wild-type PYP, which agrees well with recent transient absorption measurements. In 20% of the trajectories, we observe the formation of a photoproduct that has the carbonyl oxygen atom of the chromophore flipped by almost 180°, disrupting the hydrogen bond between the chromophore and the backbone amino group of Cys69. This observation, in combination with the fact that the mutant is photoactive, suggests that the break of the hydrogen bond is the key step in the photoactivation process rather than the double bond trans-to-cis isomerization."],["dc.identifier.doi","10.1021/ja078024u"],["dc.identifier.pmid","18293978"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/12226"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.relation.eissn","1520-5126"],["dc.title","Arginine52 controls the photoisomerization process in photoactive yellow protein"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","96"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Kidney International"],["dc.bibliographiccitation.lastpage","109"],["dc.bibliographiccitation.volume","68"],["dc.contributor.author","Heeg, MHJ"],["dc.contributor.author","Koziolek, Michael Johann"],["dc.contributor.author","Vasko, Radovan"],["dc.contributor.author","Schaefer, L."],["dc.contributor.author","Sharma, K."],["dc.contributor.author","Mueller, Gerhard A."],["dc.contributor.author","Strutz, Frank M."],["dc.date.accessioned","2018-11-07T09:23:04Z"],["dc.date.available","2018-11-07T09:23:04Z"],["dc.date.issued","2005"],["dc.description.abstract","Background. The peptide hormone relaxin has been demonstrated to exert antifibrotic effects in renal and extrarenal tissues. The aims of this study were to identify potential anti-fibrotic effects of relaxin on human renal fibroblasts in vitro and to analyze their mechanisms. Methods. All experiments were performed in established renal fibroblast cell lines and in primary cortical fibroblasts. Effects of relaxin were analyzed on cell proliferation, apoptosis, activation of renal fibroblasts, synthesis and secretion of collagen type I and fibronectin, as well as on the secretion of matrix metalloproteinases (MMPs). Effects on transforming growth factor-beta 1 (TGF-beta 1) receptor binding were analyzed by flow cytometry and on TGF-beta 1 signal transduction by immunoblot analyses for Smad4 and 7, translocation from cytosol to nucleus for Smad2 and 3 as well as for phosphorylated and unphosphorylated forms of p38, c-Jun NH2 terminal kinase (JNK) and extracellular-regulated protein kinase (ERK). Finally, specific siRNAs for Smad2 and 3 were applied to assess the signal transduction pathway. Results. After stimulation with relaxin, tyrosine phosphorylation of a 220 kD protein was demonstrated, indicating interaction with the receptor. Relaxin had only modest inhibitory effects on cell proliferation, and no effects on apoptosis. Conversely, relaxin exerted robust effects on TGF-beta 1-induced fibroblast to myofibroblast transformation as well as on matrix synthesis and secretion even at the smallest dose tested. The secretion of MMP-2 and MMP-9 was induced noticeably by all investigated relaxin concentrations. TGF-beta 1 receptor binding was not influenced by relaxin; however, it prevented Smad2 phosphorylation, translocation to nucleus, and complex formation between Smad2 and 3 indicating a possible interaction with TGF-beta 1 signaling. These findings were corroborated by studies using siRNAs to Smad2 and 3 where siRNA to Smad2 but not to Smad3 inhibited the TGF-beta 1 induction of fibronectin synthesis. There was no influence of relaxin on intracellular Smad3, Smad4, and Smad7 translocation or phosphorylation of mitogen-activated protein (MAP) kinases. Conclusion. Relaxin is a potent inhibitor of TGF-beta 1-induced extracellular matrix (ECM) synthesis and secretion as well as fibroblast activation. Furthermore, it induces ECM degradation by induction of MMP-2 and MMP-9. These effects are mediated, at least in part, by inhibition of TGF-beta 1 signaling."],["dc.identifier.doi","10.1111/j.1523-1755.2005.00384.x"],["dc.identifier.isi","000229636800009"],["dc.identifier.pmid","15954899"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/29491"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Blackwell Publishing Inc"],["dc.relation.issn","0085-2538"],["dc.title","The antifibrotic effects of relaxin in human renal fibroblasts are mediated in part by inhibition of the Smad2 pathway"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1919"],["dc.bibliographiccitation.issue","9"],["dc.bibliographiccitation.journal","Journal of Computational Chemistry"],["dc.bibliographiccitation.lastpage","1928"],["dc.bibliographiccitation.volume","32"],["dc.contributor.author","De Jong, Djurre H."],["dc.contributor.author","Schäfer, Lars V."],["dc.contributor.author","de Vries, Alex"],["dc.contributor.author","Marrink, Siewert Jan"],["dc.contributor.author","Berendsen, Herman J.C."],["dc.contributor.author","Grubmüller, Helmut"],["dc.date.accessioned","2018-02-13T09:43:38Z"],["dc.date.available","2018-02-13T09:43:38Z"],["dc.date.issued","2011-07-15"],["dc.description.abstract","With today's available computer power, free energy calculations from equilibrium molecular dynamics simulations \"via counting\" become feasible for an increasing number of reactions. An example is the dimerization reaction of transmembrane alpha-helices. If an extended simulation of the two helices covers sufficiently many dimerization and dissociation events, their binding free energy is readily derived from the fraction of time during which the two helices are observed in dimeric form. Exactly how the correct value for the free energy is to be calculated, however, is unclear, and indeed several different and contradictory approaches have been used. In particular, results obtained via Boltzmann statistics differ from those determined via the law of mass action. Here, we develop a theory that resolves this discrepancy. We show that for simulation systems containing two molecules, the dimerization free energy is given by a formula of the form ΔG ∝ ln(P(1) /P(0) ). Our theory is also applicable to high concentrations that typically have to be used in molecular dynamics simulations to keep the simulation system small, where the textbook dilute approximations fail. It also covers simulations with an arbitrary number of monomers and dimers and provides rigorous error estimates. Comparison with test simulations of a simple Lennard Jones system with various particle numbers as well as with reference free energy values obtained from radial distribution functions show full agreement for both binding free energies and dimerization statistics."],["dc.identifier.doi","10.1002/jcc.21776"],["dc.identifier.pmid","21469160"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/12196"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.relation.eissn","1096-987X"],["dc.title","Determining equilibrium constants for dimerization reactions from molecular dynamics simulations"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","13385"],["dc.bibliographiccitation.issue","36"],["dc.bibliographiccitation.journal","Proceedings of the National Academy of Sciences of the United States of America"],["dc.bibliographiccitation.lastpage","13390"],["dc.bibliographiccitation.volume","105"],["dc.contributor.author","Puchner, Elias M"],["dc.contributor.author","Alexandrovich, Alexander"],["dc.contributor.author","Kho, Ay Lin"],["dc.contributor.author","Hensen, Ulf"],["dc.contributor.author","Schäfer, Lars V."],["dc.contributor.author","Brandmeier, Birgit"],["dc.contributor.author","Gräter, Frauke"],["dc.contributor.author","Grubmüller, Helmut"],["dc.contributor.author","Gaub, Hermann"],["dc.contributor.author","Gautel, Mathias"],["dc.date.accessioned","2018-02-13T13:12:50Z"],["dc.date.available","2018-02-13T13:12:50Z"],["dc.date.issued","2008-09-09"],["dc.description.abstract","Biological responses to mechanical stress require strain-sensing molecules, whose mechanically induced conformational changes are relayed to signaling cascades mediating changes in cell and tissue properties. In vertebrate muscle, the giant elastic protein titin is involved in strain sensing via its C-terminal kinase domain (TK) at the sarcomeric M-band and contributes to the adaptation of muscle in response to changes in mechanical strain. TK is regulated in a unique dual autoinhibition mechanism by a C-terminal regulatory tail, blocking the ATP binding site, and tyrosine autoinhibition of the catalytic base. For access to the ATP binding site and phosphorylation of the autoinhibitory tyrosine, the C-terminal autoinhibitory tail needs to be removed. Here, we use AFM-based single-molecule force spectroscopy, molecular dynamics simulations, and enzymatics to study the conformational changes during strain-induced activation of human TK. We show that mechanical strain activates ATP binding before unfolding of the structural titin domains, and that TK can thus act as a biological force sensor. Furthermore, we identify the steps in which the autoinhibition of TK is mechanically relieved at low forces, leading to binding of the cosubstrate ATP and priming the enzyme for subsequent autophosphorylation and substrate turnover."],["dc.identifier.doi","10.1073/pnas.0805034105"],["dc.identifier.pmid","18765796"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/12229"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.relation.eissn","1091-6490"],["dc.relation.haserratum","/handle/2/80234"],["dc.title","Mechanoenzymatics of titin kinase"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2232"],["dc.bibliographiccitation.issue","13"],["dc.bibliographiccitation.journal","Angewandte Chemie International Edition"],["dc.bibliographiccitation.lastpage","2237"],["dc.bibliographiccitation.volume","46"],["dc.contributor.author","Schäfer, Lars V."],["dc.contributor.author","Müller, E. Matthias"],["dc.contributor.author","Gaub, Hermann E."],["dc.contributor.author","Grubmüller, Helmut"],["dc.date.accessioned","2018-04-23T11:47:48Z"],["dc.date.available","2018-04-23T11:47:48Z"],["dc.date.issued","2007"],["dc.identifier.doi","10.1002/anie.200604595"],["dc.identifier.gro","3142271"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/13399"],["dc.language.iso","en"],["dc.notes.intern","lifescience updates Crossref Import"],["dc.notes.status","final"],["dc.relation.issn","1433-7851"],["dc.title","Elastic Properties of Photoswitchable Azobenzene Polymers from Molecular Dynamics Simulations"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.peerReviewed","no"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","10996"],["dc.bibliographiccitation.issue","36"],["dc.bibliographiccitation.journal","Journal of the American Chemical Society"],["dc.bibliographiccitation.lastpage","10997"],["dc.bibliographiccitation.volume","129"],["dc.contributor.author","Boggio-Pasqua, Martial"],["dc.contributor.author","Groenhof, Gerrit"],["dc.contributor.author","Schäfer, Lars V."],["dc.contributor.author","Grubmüller, Helmut"],["dc.contributor.author","Robb, Michael A."],["dc.date.accessioned","2018-04-23T11:47:46Z"],["dc.date.available","2018-04-23T11:47:46Z"],["dc.date.issued","2007"],["dc.identifier.doi","10.1021/ja073628j"],["dc.identifier.gro","3142265"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/13393"],["dc.language.iso","en"],["dc.notes.intern","lifescience updates Crossref Import"],["dc.notes.status","final"],["dc.relation.issn","0002-7863"],["dc.title","Ultrafast Deactivation Channel for Thymine Dimerization"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.peerReviewed","no"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","13070"],["dc.bibliographiccitation.issue","37"],["dc.bibliographiccitation.journal","Proceedings of the National Academy of Sciences"],["dc.bibliographiccitation.lastpage","13074"],["dc.bibliographiccitation.volume","102"],["dc.contributor.author","Andresen, Martin"],["dc.contributor.author","Wahl, Markus C."],["dc.contributor.author","Stiel, André C."],["dc.contributor.author","Gräter, Frauke"],["dc.contributor.author","Schäfer, Lars V."],["dc.contributor.author","Trowitzsch, Simon"],["dc.contributor.author","Weber, Gert"],["dc.contributor.author","Eggeling, Christian"],["dc.contributor.author","Grubmüller, Helmut"],["dc.contributor.author","Hell, Stefan W."],["dc.contributor.author","Jakobs, Stefan"],["dc.date.accessioned","2017-09-07T11:54:19Z"],["dc.date.available","2017-09-07T11:54:19Z"],["dc.date.issued","2005"],["dc.description.abstract","Proteins that can be reversibly photoswitched between a fluorescent and a nonfluorescent state bear enormous potential in diverse fields, such as data storage, in vivo protein tracking, and subdiffraction resolution light microscopy. However, these proteins could hitherto not live up to their full potential because the molecular switching mechanism is not resolved. Here, we clarify the molecular photoswitching mechanism of asFP595, a green fluorescent protein (GFP)-like protein that can be transferred from a nonfluorescent \"off\" to a fluorescent \"on\" state and back again, by green and blue light, respectively. To this end, we establish reversible photoswitching of fluorescence in whole protein crystals and show that the switching kinetics in the crystal is identical with that in solution. Subsequent x-ray analysis demonstrated that upon the absorption of a green photon, the chromophore isomerizes from a trans (off) to a cis (on) state. Molecular dynamics calculations suggest that isomerization occurs through a bottom hula twist mechanism with concomitant rotation of both bonds of the chromophoric methine ring bridge. This insight into the switching mechanism should facilitate the targeted design of photo-switchable proteins. Reversible photoswitching of the protein chromophore system within intact crystals also constitutes a step toward the use of fluorescent proteins in three-dimensional data recording."],["dc.identifier.doi","10.1073/pnas.0502772102"],["dc.identifier.gro","3143804"],["dc.identifier.isi","000231916300014"],["dc.identifier.pmid","16135569"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/1359"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.issn","0027-8424"],["dc.title","Structure and mechanism of the reversible photoswitch of a fluorescent protein"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]