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The HAMP signal relay domain adopts multiple conformational states through collective piston and tilt motions.

Zhu L, Bolhuis PG, Vreede J - PLoS Comput. Biol. (2013)

Bottom Line: These simulations revealed additional conformational states that differ in the tilt angles between the helices as well as the relative piston shifts of the helices relative to each other.Our results indicate that HAMP can access additional conformational states characterized by piston motion.Our results provide insights into the conformational changes that underlie the signaling mechanism involving HAMP.

View Article: PubMed Central - PubMed

Affiliation: Van 't Hoff Institute for Molecular Sciences, University of Amsterdam, Amsterdam, The Netherlands.

ABSTRACT
The HAMP domain is a linker region in prokaryotic sensor proteins and relays input signals to the transmitter domain and vice versa. Functional as a dimer, the structure of HAMP shows a parallel coiled-coil motif comprising four helices. To date, it is unclear how HAMP can relay signals from one domain to another, although several models exist. In this work, we use molecular simulation to test the hypothesis that HAMP adopts different conformations, one of which represents an active, signal-relaying configuration, and another an inactive, resting state. We first performed molecular dynamics simulation on the prototype HAMP domain Af1503 from Archaeoglobus fulgidus. We explored its conformational space by taking the structure of the A291F mutant disabling HAMP activity as a starting point. These simulations revealed additional conformational states that differ in the tilt angles between the helices as well as the relative piston shifts of the helices relative to each other. By enhancing the sampling in a metadynamics set up, we investigated three mechanistic models for HAMP signal transduction. Our results indicate that HAMP can access additional conformational states characterized by piston motion. Furthermore, the piston motion of the N-terminal helix of one monomer is directly correlated with the opposite piston motion of the C-terminal helix of the other monomer. The change in piston motion is accompanied by a change in tilt angle between the monomers, thus revealing that HAMP exhibits a collective motion, i.e. a combination of changes in tilt angles and a piston-like displacement. Our results provide insights into the conformational changes that underlie the signaling mechanism involving HAMP.

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Two dimensional bias on piston motions.In the metadynamics simulations the biasing potential was applied to (A)  and ; (B)  and . The results are shown as free energy profiles in the following projections: (A1,B1)  versus ; (A2,B2)  versus ; (A3,B3)  versus ; (A4,B4)  versus . (A1) and (B2) show the free energy landscapes of biased CVs, the other subplots are corresponding reweighted free energy surfaces. Stars indicate the CV on which the bias was applied. Labels indicate stable states. Contour lines are rendered every . The two-dimensional metadynamics simulations show that the piston motions of helices N1 and C2 are oppositely correlated, and that this correlation also exists for the C1,N2 pair.
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pcbi-1002913-g006: Two dimensional bias on piston motions.In the metadynamics simulations the biasing potential was applied to (A) and ; (B) and . The results are shown as free energy profiles in the following projections: (A1,B1) versus ; (A2,B2) versus ; (A3,B3) versus ; (A4,B4) versus . (A1) and (B2) show the free energy landscapes of biased CVs, the other subplots are corresponding reweighted free energy surfaces. Stars indicate the CV on which the bias was applied. Labels indicate stable states. Contour lines are rendered every . The two-dimensional metadynamics simulations show that the piston motions of helices N1 and C2 are oppositely correlated, and that this correlation also exists for the C1,N2 pair.

Mentions: We have found a negative correlation between the piston shifts of the N-terminal helix of one monomer and the C-terminal helix of the other monomer, (see FIG. 5-C1). To investigate this correlation further, we performed a two-dimensional metadynamics run, biasing both and . FIG. 6-A1 shows the resulting two-dimensional free energy surface. The profile reveals two minima that are very similar to the states and identified in the conventional MD study and the one-dimensional metadynamics simulation biasing a single piston shift. The piston shift of the N1-helix is strongly anti-correlated with the piston shift of the C2-helix. In FIG. 6-A2, the reweighted free energy profile as a function of and shows that piston shifts in this helical pair are not correlated, as no change occurs for , when shows a piston shift (see FIG. 6-A3, A4).


The HAMP signal relay domain adopts multiple conformational states through collective piston and tilt motions.

Zhu L, Bolhuis PG, Vreede J - PLoS Comput. Biol. (2013)

Two dimensional bias on piston motions.In the metadynamics simulations the biasing potential was applied to (A)  and ; (B)  and . The results are shown as free energy profiles in the following projections: (A1,B1)  versus ; (A2,B2)  versus ; (A3,B3)  versus ; (A4,B4)  versus . (A1) and (B2) show the free energy landscapes of biased CVs, the other subplots are corresponding reweighted free energy surfaces. Stars indicate the CV on which the bias was applied. Labels indicate stable states. Contour lines are rendered every . The two-dimensional metadynamics simulations show that the piston motions of helices N1 and C2 are oppositely correlated, and that this correlation also exists for the C1,N2 pair.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3585426&req=5

pcbi-1002913-g006: Two dimensional bias on piston motions.In the metadynamics simulations the biasing potential was applied to (A) and ; (B) and . The results are shown as free energy profiles in the following projections: (A1,B1) versus ; (A2,B2) versus ; (A3,B3) versus ; (A4,B4) versus . (A1) and (B2) show the free energy landscapes of biased CVs, the other subplots are corresponding reweighted free energy surfaces. Stars indicate the CV on which the bias was applied. Labels indicate stable states. Contour lines are rendered every . The two-dimensional metadynamics simulations show that the piston motions of helices N1 and C2 are oppositely correlated, and that this correlation also exists for the C1,N2 pair.
Mentions: We have found a negative correlation between the piston shifts of the N-terminal helix of one monomer and the C-terminal helix of the other monomer, (see FIG. 5-C1). To investigate this correlation further, we performed a two-dimensional metadynamics run, biasing both and . FIG. 6-A1 shows the resulting two-dimensional free energy surface. The profile reveals two minima that are very similar to the states and identified in the conventional MD study and the one-dimensional metadynamics simulation biasing a single piston shift. The piston shift of the N1-helix is strongly anti-correlated with the piston shift of the C2-helix. In FIG. 6-A2, the reweighted free energy profile as a function of and shows that piston shifts in this helical pair are not correlated, as no change occurs for , when shows a piston shift (see FIG. 6-A3, A4).

Bottom Line: These simulations revealed additional conformational states that differ in the tilt angles between the helices as well as the relative piston shifts of the helices relative to each other.Our results indicate that HAMP can access additional conformational states characterized by piston motion.Our results provide insights into the conformational changes that underlie the signaling mechanism involving HAMP.

View Article: PubMed Central - PubMed

Affiliation: Van 't Hoff Institute for Molecular Sciences, University of Amsterdam, Amsterdam, The Netherlands.

ABSTRACT
The HAMP domain is a linker region in prokaryotic sensor proteins and relays input signals to the transmitter domain and vice versa. Functional as a dimer, the structure of HAMP shows a parallel coiled-coil motif comprising four helices. To date, it is unclear how HAMP can relay signals from one domain to another, although several models exist. In this work, we use molecular simulation to test the hypothesis that HAMP adopts different conformations, one of which represents an active, signal-relaying configuration, and another an inactive, resting state. We first performed molecular dynamics simulation on the prototype HAMP domain Af1503 from Archaeoglobus fulgidus. We explored its conformational space by taking the structure of the A291F mutant disabling HAMP activity as a starting point. These simulations revealed additional conformational states that differ in the tilt angles between the helices as well as the relative piston shifts of the helices relative to each other. By enhancing the sampling in a metadynamics set up, we investigated three mechanistic models for HAMP signal transduction. Our results indicate that HAMP can access additional conformational states characterized by piston motion. Furthermore, the piston motion of the N-terminal helix of one monomer is directly correlated with the opposite piston motion of the C-terminal helix of the other monomer. The change in piston motion is accompanied by a change in tilt angle between the monomers, thus revealing that HAMP exhibits a collective motion, i.e. a combination of changes in tilt angles and a piston-like displacement. Our results provide insights into the conformational changes that underlie the signaling mechanism involving HAMP.

Show MeSH
Related in: MedlinePlus