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Mapping the Conformation Space of Wildtype and Mutant H-Ras with a Memetic, Cellular, and Multiscale Evolutionary Algorithm.

Clausen R, Ma B, Nussinov R, Shehu A - PLoS Comput. Biol. (2015)

Bottom Line: Many Ras mutations are oncogenic, but detailed energy landscapes have not been reported until now.Analysis of SIfTER-computed energy landscapes for the wildtype and two oncogenic variants, G12V and Q61L, suggests that these mutations cause constitutive activation through two different mechanisms.G12V directly affects binding specificity while leaving the energy landscape largely unchanged, whereas Q61L has pronounced, starker effects on the landscape.

View Article: PubMed Central - PubMed

Affiliation: Department of Computer Science, George Mason University, Fairfax, Virginia, United States of America.

ABSTRACT
An important goal in molecular biology is to understand functional changes upon single-point mutations in proteins. Doing so through a detailed characterization of structure spaces and underlying energy landscapes is desirable but continues to challenge methods based on Molecular Dynamics. In this paper we propose a novel algorithm, SIfTER, which is based instead on stochastic optimization to circumvent the computational challenge of exploring the breadth of a protein's structure space. SIfTER is a data-driven evolutionary algorithm, leveraging experimentally-available structures of wildtype and variant sequences of a protein to define a reduced search space from where to efficiently draw samples corresponding to novel structures not directly observed in the wet laboratory. The main advantage of SIfTER is its ability to rapidly generate conformational ensembles, thus allowing mapping and juxtaposing landscapes of variant sequences and relating observed differences to functional changes. We apply SIfTER to variant sequences of the H-Ras catalytic domain, due to the prominent role of the Ras protein in signaling pathways that control cell proliferation, its well-studied conformational switching, and abundance of documented mutations in several human tumors. Many Ras mutations are oncogenic, but detailed energy landscapes have not been reported until now. Analysis of SIfTER-computed energy landscapes for the wildtype and two oncogenic variants, G12V and Q61L, suggests that these mutations cause constitutive activation through two different mechanisms. G12V directly affects binding specificity while leaving the energy landscape largely unchanged, whereas Q61L has pronounced, starker effects on the landscape. An implementation of SIfTER is made available at http://www.cs.gmu.edu/~ashehu/?q=OurTools. We believe SIfTER is useful to the community to answer the question of how sequence mutations affect the function of a protein, when there is an abundance of experimental structures that can be exploited to reconstruct an energy landscape that would be computationally impractical to do via Molecular Dynamics.

No MeSH data available.


Related in: MedlinePlus

Structural States Corresponding to SIfTER-obtained Basins.Top panel: A representative conformation is drawn from each of the four basins obtained for the WT H-Ras by SIfTER. Different colors are used to distinguish conformations and see the breadth of the structural change captured by the four basins corresponding to the stable and semi-stable states. Yellow corresponds to the Conf2 basin, purple to the Conf1 basin, green to the Off basin, and blue to the On basin. Conformations are drawn in ribbon representation. The GTP/GDP ligand is also shown, drawn in a ball-and-stick representation. Bottom panel: Conformations representative of a given basin in each of the three sequences are superimposed and drawn in gray. A crystallographic structure projecting to each of the four basins is also drawn (in red). Conformations are drawn in ribbon representation. The side chain of V12 is drawn in purple and that of L61 in yellow in ball-and-stick representation. The GTP/GDP ligand is also drawn in ball-and-stick representation. Pymol [44] is used for rendering.
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pcbi.1004470.g006: Structural States Corresponding to SIfTER-obtained Basins.Top panel: A representative conformation is drawn from each of the four basins obtained for the WT H-Ras by SIfTER. Different colors are used to distinguish conformations and see the breadth of the structural change captured by the four basins corresponding to the stable and semi-stable states. Yellow corresponds to the Conf2 basin, purple to the Conf1 basin, green to the Off basin, and blue to the On basin. Conformations are drawn in ribbon representation. The GTP/GDP ligand is also shown, drawn in a ball-and-stick representation. Bottom panel: Conformations representative of a given basin in each of the three sequences are superimposed and drawn in gray. A crystallographic structure projecting to each of the four basins is also drawn (in red). Conformations are drawn in ribbon representation. The side chain of V12 is drawn in purple and that of L61 in yellow in ball-and-stick representation. The GTP/GDP ligand is also drawn in ball-and-stick representation. Pymol [44] is used for rendering.

Mentions: The structural states corresponding to each of the 4 basins recovered by SIfTER for WT H-Ras are shown in Fig 6 (top panel). 4 conformations representing each of these 4 basins are superimposed over one another. Superimposition of these conformations allows visualizing the slight structural changes associated with the four different structural states found by SIfTER.


Mapping the Conformation Space of Wildtype and Mutant H-Ras with a Memetic, Cellular, and Multiscale Evolutionary Algorithm.

Clausen R, Ma B, Nussinov R, Shehu A - PLoS Comput. Biol. (2015)

Structural States Corresponding to SIfTER-obtained Basins.Top panel: A representative conformation is drawn from each of the four basins obtained for the WT H-Ras by SIfTER. Different colors are used to distinguish conformations and see the breadth of the structural change captured by the four basins corresponding to the stable and semi-stable states. Yellow corresponds to the Conf2 basin, purple to the Conf1 basin, green to the Off basin, and blue to the On basin. Conformations are drawn in ribbon representation. The GTP/GDP ligand is also shown, drawn in a ball-and-stick representation. Bottom panel: Conformations representative of a given basin in each of the three sequences are superimposed and drawn in gray. A crystallographic structure projecting to each of the four basins is also drawn (in red). Conformations are drawn in ribbon representation. The side chain of V12 is drawn in purple and that of L61 in yellow in ball-and-stick representation. The GTP/GDP ligand is also drawn in ball-and-stick representation. Pymol [44] is used for rendering.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556523&req=5

pcbi.1004470.g006: Structural States Corresponding to SIfTER-obtained Basins.Top panel: A representative conformation is drawn from each of the four basins obtained for the WT H-Ras by SIfTER. Different colors are used to distinguish conformations and see the breadth of the structural change captured by the four basins corresponding to the stable and semi-stable states. Yellow corresponds to the Conf2 basin, purple to the Conf1 basin, green to the Off basin, and blue to the On basin. Conformations are drawn in ribbon representation. The GTP/GDP ligand is also shown, drawn in a ball-and-stick representation. Bottom panel: Conformations representative of a given basin in each of the three sequences are superimposed and drawn in gray. A crystallographic structure projecting to each of the four basins is also drawn (in red). Conformations are drawn in ribbon representation. The side chain of V12 is drawn in purple and that of L61 in yellow in ball-and-stick representation. The GTP/GDP ligand is also drawn in ball-and-stick representation. Pymol [44] is used for rendering.
Mentions: The structural states corresponding to each of the 4 basins recovered by SIfTER for WT H-Ras are shown in Fig 6 (top panel). 4 conformations representing each of these 4 basins are superimposed over one another. Superimposition of these conformations allows visualizing the slight structural changes associated with the four different structural states found by SIfTER.

Bottom Line: Many Ras mutations are oncogenic, but detailed energy landscapes have not been reported until now.Analysis of SIfTER-computed energy landscapes for the wildtype and two oncogenic variants, G12V and Q61L, suggests that these mutations cause constitutive activation through two different mechanisms.G12V directly affects binding specificity while leaving the energy landscape largely unchanged, whereas Q61L has pronounced, starker effects on the landscape.

View Article: PubMed Central - PubMed

Affiliation: Department of Computer Science, George Mason University, Fairfax, Virginia, United States of America.

ABSTRACT
An important goal in molecular biology is to understand functional changes upon single-point mutations in proteins. Doing so through a detailed characterization of structure spaces and underlying energy landscapes is desirable but continues to challenge methods based on Molecular Dynamics. In this paper we propose a novel algorithm, SIfTER, which is based instead on stochastic optimization to circumvent the computational challenge of exploring the breadth of a protein's structure space. SIfTER is a data-driven evolutionary algorithm, leveraging experimentally-available structures of wildtype and variant sequences of a protein to define a reduced search space from where to efficiently draw samples corresponding to novel structures not directly observed in the wet laboratory. The main advantage of SIfTER is its ability to rapidly generate conformational ensembles, thus allowing mapping and juxtaposing landscapes of variant sequences and relating observed differences to functional changes. We apply SIfTER to variant sequences of the H-Ras catalytic domain, due to the prominent role of the Ras protein in signaling pathways that control cell proliferation, its well-studied conformational switching, and abundance of documented mutations in several human tumors. Many Ras mutations are oncogenic, but detailed energy landscapes have not been reported until now. Analysis of SIfTER-computed energy landscapes for the wildtype and two oncogenic variants, G12V and Q61L, suggests that these mutations cause constitutive activation through two different mechanisms. G12V directly affects binding specificity while leaving the energy landscape largely unchanged, whereas Q61L has pronounced, starker effects on the landscape. An implementation of SIfTER is made available at http://www.cs.gmu.edu/~ashehu/?q=OurTools. We believe SIfTER is useful to the community to answer the question of how sequence mutations affect the function of a protein, when there is an abundance of experimental structures that can be exploited to reconstruct an energy landscape that would be computationally impractical to do via Molecular Dynamics.

No MeSH data available.


Related in: MedlinePlus