Signals of LOV1: a computer simulation study on the wildtype LOV1-domain of Chlamydomonas reinhardtii and its mutants

Peter, Emanuel K.; Dick, Bernhard; Baeurle, Stephan A.

doi:10.1007/s00894-011-1165-6

Cited by 18 publications

(23 citation statements)

References 53 publications

(69 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…From several experimental and theoretical investigations, 8,14,[51][52][53][54] it is well known that the three amino acids Gln513, Asn492, and Asn482 are essential in triggering the signaling pathway of the AsLOV2-Jα-as well as the PA-Rac1-system. We assume that these amino acids can carry out the following rate-dependent transformation processes, i.e., (1) side chain rotation, (2) H-bond formation, and (3) H-bond breakage, which are included in the list of events of the RB-KMC algorithm.…”

Section: Residue-based Kmcmentioning

confidence: 99%

A novel computer simulation method for simulating the multiscale transduction dynamics of signal proteins

Peter

Dick

Baeurle

2012

The Journal of Chemical Physics

Self Cite

View full text Add to dashboard Cite

Signal proteins are able to adapt their response to a change in the environment, governing in this way a broad variety of important cellular processes in living systems. While conventional moleculardynamics (MD) techniques can be used to explore the early signaling pathway of these protein systems at atomistic resolution, the high computational costs limit their usefulness for the elucidation of the multiscale transduction dynamics of most signaling processes, occurring on experimental timescales. To cope with the problem, we present in this paper a novel multiscale-modeling method, based on a combination of the kinetic Monte-Carlo-and MD-technique, and demonstrate its suitability for investigating the signaling behavior of the photoswitch light-oxygen-voltage-2-Jα domain from Avena Sativa (AsLOV2-Jα) and an AsLOV2-Jα-regulated photoactivable Rac1-GTPase (PA-Rac1), recently employed to control the motility of cancer cells through light stimulus. More specifically, we show that their signaling pathways begin with a residual re-arrangement and subsequent H-bond formation of amino acids near to the flavin-mononucleotide chromophore, causing a coupling between β-strands and subsequent detachment of a peripheral α-helix from the AsLOV2-domain. In the case of the PA-Rac1 system we find that this latter process induces the release of the AsLOV2-inhibitor from the switchII-activation site of the GTPase, enabling signal activation through effector-protein binding. These applications demonstrate that our approach reliably reproduces the signaling pathways of complex signal proteins, ranging from nanoseconds up to seconds at affordable computational costs.

show abstract

Section: Residue-based Kmcmentioning

confidence: 99%

A novel computer simulation method for simulating the multiscale transduction dynamics of signal proteins

Peter

Dick

Baeurle

2012

The Journal of Chemical Physics

Self Cite

View full text Add to dashboard Cite

show abstract

“…Several recent MD studies on LOV domains have highlighted the role of rotamerization of a highly conserved glutamine residue (Q513 in AsPhot1-LOV2). In a series of simulations on LOV domains from various organisms, Baeurle and coworkers have highlighted the importance of a light-induced hydrogen bond between Q513 and N492 (using AsPhot1-LOV2 numbering) in AsPhot1-LOV2 44,46 and N. crassa Vivid 45 (but not in a LOV1 domain from C. reindardtii 47 . In the specific case of AsPhot1-LOV2, they concluded that disruption of the J α -LOV2 interface was triggered by stress due to the increased coupling of the H β and I β strands 44,46 , and subsequent breakage of Q497-D540 and Q479-E518 hydrogen bonds 44 .…”

Section: Introductionmentioning

confidence: 99%

Signaling mechanisms of LOV domains: new insights from molecular dynamics studies

Freddolino

Gardner

Schulten

2013

Photochem Photobiol Sci

125

View full text Add to dashboard Cite

Phototropins are one of several classes of photoreceptors used by plants and algae to respond to light. These proteins contain flavin-binding LOV (Light-Oxygen-Voltage) domains that form covalent cysteine-flavin adducts upon exposure to blue light, leading to the enhancement of phototropin kinase activity. Several lines of evidence suggest that adduct formation in the phototropin LOV2 domains leads to the dissociation of an alpha helix (Jα) from these domains as part of the light-induced activation process. However, crystal structures of LOV domains both in the presence and absence of the Jα helix show very few differences between dark and illuminated states, and thus the precise mechanism through which adduct formation triggers helical dissociation remains poorly understood. Using Avena sativa phototropin 1 LOV2 as a model system, we have studied the interactions of the LOV domain core with the Jα helix through a series of equilibrium molecular dynamics simulations. Here we show that conformational transitions of a conserved glutamine residue in the flavin binding pocket are coupled to altered dynamics of the Jα helix both through a shift in dynamics of the main β-sheet of the LOV domain core and through a secondary pathway involving the N-terminal A′α helix.

show abstract

“…To study the functional behavior of complex protein systems in nonequilibrium situations, we have recently introduced a novel noninvasive thermostating strategy, relying on the molecular dynamics (MD) algorithm,10–12 and demonstrated its usefulness to explore the early stages of the switching mechanism of the AsLOV2‐Jα photosensor at the molecular level. The so‐called noninvasive MD technique permits to sample the protein's configurations far from equilibrium and to follow its natural dynamics under solvent‐mediated thermostating control 10.…”

Section: Introductionmentioning

confidence: 99%

Regulatory mechanism of the light‐activable allosteric switch LOV–TAP for the control of DNA binding: A computer simulation study

2012

Self Cite

View full text Add to dashboard Cite

The spatio-temporal control of gene expression is fundamental to elucidate cell proliferation and deregulation phenomena in living systems. Novel approaches based on light-sensitive multiprotein complexes have recently been devised, showing promising perspectives for the noninvasive and reversible modulation of the DNA-transcriptional activity in vivo. This has lately been demonstrated in a striking way through the generation of the artificial protein construct light-oxygen-voltage (LOV)-tryptophan-activated protein (TAP), in which the LOV-2-Jα photoswitch of phototropin1 from Avena sativa (AsLOV2-Jα) has been ligated to the tryptophan-repressor (TrpR) protein from Escherichia coli. Although tremendous progress has been achieved on the generation of such protein constructs, a detailed understanding of their functioning as opto-genetical tools is still in its infancy. Here, we elucidate the early stages of the light-induced regulatory mechanism of LOV-TAP at the molecular level, using the noninvasive molecular dynamics simulation technique. More specifically, we find that Cys450-FMN-adduct formation in the AsLOV2-Jα-binding pocket after photoexcitation induces the cleavage of the peripheral Jα-helix from the LOV core, causing a change of its polarity and electrostatic attraction of the photoswitch onto the DNA surface. This goes along with the flexibilization through unfolding of a hairpin-like helix-loop-helix region interlinking the AsLOV2-Jα- and TrpR-domains, ultimately enabling the condensation of LOV-TAP onto the DNA surface. By contrast, in the dark state the AsLOV2-Jα photoswitch remains inactive and exerts a repulsive electrostatic force on the DNA surface. This leads to a distortion of the hairpin region, which finally relieves its tension by causing the disruption of LOV-TAP from the DNA.

show abstract

Signals of LOV1: a computer simulation study on the wildtype LOV1-domain of Chlamydomonas reinhardtii and its mutants

Cited by 18 publications

References 53 publications

A novel computer simulation method for simulating the multiscale transduction dynamics of signal proteins

A novel computer simulation method for simulating the multiscale transduction dynamics of signal proteins

Signaling mechanisms of LOV domains: new insights from molecular dynamics studies

Regulatory mechanism of the light‐activable allosteric switch LOV–TAP for the control of DNA binding: A computer simulation study

Contact Info

Product

Resources

About