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Deciphering Solution Scattering Data with Experimentally Guided Molecular Dynamics Simulations.

Björling A, Niebling S, Marcellini M, van der Spoel D, Westenhoff S - J Chem Theory Comput (2015)

Bottom Line: Extracting structural information from the resulting difference X-ray scattering data is a daunting task.Therefore, the energy landscape is biased toward conformations that agree with experimental data.We describe and verify the method, and we provide an implementation in GROMACS.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg , SE-405 30 Gothenburg, Sweden.

ABSTRACT

Time-resolved X-ray solution scattering is an increasingly popular method to measure conformational changes in proteins. Extracting structural information from the resulting difference X-ray scattering data is a daunting task. We present a method in which the limited but precious information encoded in such scattering curves is combined with the chemical knowledge of molecular force fields. The molecule of interest is then refined toward experimental data using molecular dynamics simulation. Therefore, the energy landscape is biased toward conformations that agree with experimental data. We describe and verify the method, and we provide an implementation in GROMACS.

No MeSH data available.


Method validation against the lysine/arginine/ornithine-bindingprotein (LAO). (A) Unrestrained simulations of the apo, holo, and lysine-free holo states.(B) XS-guided MD trajectories aiming at the apo state,starting from the lysine-free holo state, with variouscoupling strengths kχ. The plotshows RMSD:s compared to initial and target structures, as well asthe evolution of the scattering energy. (C) 25 scattering curves,extracted from the second half of the 30 kJ/mol run, together withthe target curve (thick line). (D) Graphical representation of the apo (red) and holo (orange) conformations.The right-hand model also shows a trajectory view over the secondhalf of the 30 kJ/mol run. The hinge axis is indicated.
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fig2: Method validation against the lysine/arginine/ornithine-bindingprotein (LAO). (A) Unrestrained simulations of the apo, holo, and lysine-free holo states.(B) XS-guided MD trajectories aiming at the apo state,starting from the lysine-free holo state, with variouscoupling strengths kχ. The plotshows RMSD:s compared to initial and target structures, as well asthe evolution of the scattering energy. (C) 25 scattering curves,extracted from the second half of the 30 kJ/mol run, together withthe target curve (thick line). (D) Graphical representation of the apo (red) and holo (orange) conformations.The right-hand model also shows a trajectory view over the secondhalf of the 30 kJ/mol run. The hinge axis is indicated.

Mentions: The lysine/arginine/ornithine-bindingprotein (LAO) from Salmonella typhimurium undergoes large-scale domain movements when binding ligands.46,50 Specifically, lysine binding causes one of its domains to rotate52° about an axis formed by two hinge points located on adjacentbeta strand termini. The movement is shown in Figure 2D. Reproducing this structural change constitutes a more complex,albeit hypothetical, test case for the XS-guided MD method.


Deciphering Solution Scattering Data with Experimentally Guided Molecular Dynamics Simulations.

Björling A, Niebling S, Marcellini M, van der Spoel D, Westenhoff S - J Chem Theory Comput (2015)

Method validation against the lysine/arginine/ornithine-bindingprotein (LAO). (A) Unrestrained simulations of the apo, holo, and lysine-free holo states.(B) XS-guided MD trajectories aiming at the apo state,starting from the lysine-free holo state, with variouscoupling strengths kχ. The plotshows RMSD:s compared to initial and target structures, as well asthe evolution of the scattering energy. (C) 25 scattering curves,extracted from the second half of the 30 kJ/mol run, together withthe target curve (thick line). (D) Graphical representation of the apo (red) and holo (orange) conformations.The right-hand model also shows a trajectory view over the secondhalf of the 30 kJ/mol run. The hinge axis is indicated.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4325560&req=5

fig2: Method validation against the lysine/arginine/ornithine-bindingprotein (LAO). (A) Unrestrained simulations of the apo, holo, and lysine-free holo states.(B) XS-guided MD trajectories aiming at the apo state,starting from the lysine-free holo state, with variouscoupling strengths kχ. The plotshows RMSD:s compared to initial and target structures, as well asthe evolution of the scattering energy. (C) 25 scattering curves,extracted from the second half of the 30 kJ/mol run, together withthe target curve (thick line). (D) Graphical representation of the apo (red) and holo (orange) conformations.The right-hand model also shows a trajectory view over the secondhalf of the 30 kJ/mol run. The hinge axis is indicated.
Mentions: The lysine/arginine/ornithine-bindingprotein (LAO) from Salmonella typhimurium undergoes large-scale domain movements when binding ligands.46,50 Specifically, lysine binding causes one of its domains to rotate52° about an axis formed by two hinge points located on adjacentbeta strand termini. The movement is shown in Figure 2D. Reproducing this structural change constitutes a more complex,albeit hypothetical, test case for the XS-guided MD method.

Bottom Line: Extracting structural information from the resulting difference X-ray scattering data is a daunting task.Therefore, the energy landscape is biased toward conformations that agree with experimental data.We describe and verify the method, and we provide an implementation in GROMACS.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg , SE-405 30 Gothenburg, Sweden.

ABSTRACT

Time-resolved X-ray solution scattering is an increasingly popular method to measure conformational changes in proteins. Extracting structural information from the resulting difference X-ray scattering data is a daunting task. We present a method in which the limited but precious information encoded in such scattering curves is combined with the chemical knowledge of molecular force fields. The molecule of interest is then refined toward experimental data using molecular dynamics simulation. Therefore, the energy landscape is biased toward conformations that agree with experimental data. We describe and verify the method, and we provide an implementation in GROMACS.

No MeSH data available.