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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

Comparison of Energy Landscapes Obtained by SIfTER for each H-Ras sequence.Obtained Rosetta and AMBER energy landscapes are shown for WT, G12V, and Q61L H-Ras. The location of the inactive and active structural states of H-Ras are indicated by the respective On and Off annotations. Other structural states corresponding to novel, observed basins in the landscapes are annotated by Conf1 and Conf2.
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pcbi.1004470.g005: Comparison of Energy Landscapes Obtained by SIfTER for each H-Ras sequence.Obtained Rosetta and AMBER energy landscapes are shown for WT, G12V, and Q61L H-Ras. The location of the inactive and active structural states of H-Ras are indicated by the respective On and Off annotations. Other structural states corresponding to novel, observed basins in the landscapes are annotated by Conf1 and Conf2.

Mentions: The Rosetta and Amber landscapes for each H-Ras sequence studied here are shown in Fig 5. The left column shows the Rosetta score12 landscapes, and the right column shows the AMBER ff12SB landscapes. The top row shows the landscapes obtained for the WT, the middle row shows the landscapes obtained for the G12V variant, and the bottom row shows the landscapes obtained for the Q61L variant. We note that the color bars do not show absolute energy values, but differences from the lowest-energy value obtained for each sequence. This allows focusing on relative scales rather than absolute energy values, which can be different among energy functions.


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)

Comparison of Energy Landscapes Obtained by SIfTER for each H-Ras sequence.Obtained Rosetta and AMBER energy landscapes are shown for WT, G12V, and Q61L H-Ras. The location of the inactive and active structural states of H-Ras are indicated by the respective On and Off annotations. Other structural states corresponding to novel, observed basins in the landscapes are annotated by Conf1 and Conf2.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi.1004470.g005: Comparison of Energy Landscapes Obtained by SIfTER for each H-Ras sequence.Obtained Rosetta and AMBER energy landscapes are shown for WT, G12V, and Q61L H-Ras. The location of the inactive and active structural states of H-Ras are indicated by the respective On and Off annotations. Other structural states corresponding to novel, observed basins in the landscapes are annotated by Conf1 and Conf2.
Mentions: The Rosetta and Amber landscapes for each H-Ras sequence studied here are shown in Fig 5. The left column shows the Rosetta score12 landscapes, and the right column shows the AMBER ff12SB landscapes. The top row shows the landscapes obtained for the WT, the middle row shows the landscapes obtained for the G12V variant, and the bottom row shows the landscapes obtained for the Q61L variant. We note that the color bars do not show absolute energy values, but differences from the lowest-energy value obtained for each sequence. This allows focusing on relative scales rather than absolute energy values, which can be different among energy functions.

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