A PCA-guided Search Algorithm to Probe the Conformational Space of the Ras Protein

We present an algorithm to probe the conformational space of Ras, a critical enzyme that employs conformational switching for its biological activity. The algorithm is guided by experimental data on crystallographic structures of wildtype and mutant Ras. A principal component analysis (PCA) over these structures provides search directions, which are used in combination with energetic refinement to sample low-energy conformations of Ras. Our results show that experimental structures are reproduced, and the space is further populated with novel structures, warranting further investigation into structural characterization of Ras.

[1]  A. Fernández-Medarde,et al.  Ras in cancer and developmental diseases. , 2011, Genes & cancer.

[2]  Amarda Shehu,et al.  In Search of the protein Native State with a Probabilistic Sampling Approach , 2011, J. Bioinform. Comput. Biol..

[3]  James Andrew McCammon,et al.  Ras Conformational Switching: Simulating Nucleotide-Dependent Conformational Transitions with Accelerated Molecular Dynamics , 2009, PLoS Comput. Biol..

[4]  T. Siméon,et al.  An NMA‐guided path planning approach for computing large‐amplitude conformational changes in proteins , 2007, Proteins.

[5]  Amarda Shehu,et al.  Basin Hopping as a General and Versatile Optimization Framework for the Characterization of Biological Macromolecules , 2012, Adv. Artif. Intell..

[6]  Amarda Shehu,et al.  A robotics-inspired method to sample conformational paths connecting known functionally-relevant structures in protein systems , 2012, 2012 IEEE International Conference on Bioinformatics and Biomedicine Workshops.

[7]  Amarda Shehu,et al.  Efficient basin hopping in the protein energy surface , 2012, 2012 IEEE International Conference on Bioinformatics and Biomedicine.

[8]  Amarda Shehu,et al.  Populating Local Minima in the Protein Conformational Space , 2011, 2011 IEEE International Conference on Bioinformatics and Biomedicine.

[9]  Dominik Gront,et al.  Backbone building from quadrilaterals: A fast and accurate algorithm for protein backbone reconstruction from alpha carbon coordinates , 2007, J. Comput. Chem..

[10]  Amarda Shehu,et al.  Enhancing Sampling of the Conformational Space Near the Protein Native State , 2010, BIONETICS.