Yifan Song, Cyrus’ Chief Science Officer, contributes development to major aspects of Rosetta code for de novo design of hyperstable constrained peptides published in Nature

Article Abstract: Naturally occurring, pharmacologically active peptides constrained with covalent crosslinks generally have shapes that have evolved to fit precisely into binding pockets on their targets. Such peptides can have excellent pharmaceutical properties, combining the stability and tissue penetration of small-molecule drugs with the specificity of much larger protein therapeutics. The ability to design constrained peptides with precisely specified tertiary structures would enable the design of shape-complementary inhibitors of arbitrary targets. Here we describe the development of computational methods for accurate de novo design of conformationally restricted peptides, and the use of these methods to design 18–47 residue, disulfide-crosslinked peptides, a subset of which are heterochiral and/or N–C backbone-cyclized. Both genetically encodable and non-canonical peptides are exceptionally stable to thermal and chemical denaturation, and 12 experimentally determined X-ray and NMR structures are nearly identical to the computational design models. The computational design methods and stable scaffolds presented here provide the basis for development of a new generation of peptide-based drugs.

(Nature, vol. 538, p. 329-335, 2016)

http://www.nature.com/nature/journal/v538/n7625/abs/nature19791.html

 

Yifan Song, Cyrus’ Chief Science Officer, publishes work on improved cryo-electron-microscopy protein structures using Rosetta software in Nature Methods.

Article Abstract: We describe a general approach for refining protein structure models on the basis of cryo-electron microscopy maps with near-atomic resolution. The method integrates Monte Carlo sampling with local density-guided optimization, Rosetta all-atom refinement and real-space B-factor fitting. In tests on experimental maps of three different systems with 4.5-Å resolution or better, the method consistently produced models with atomic-level accuracy largely independently of starting-model quality, and it outperformed the molecular dynamics–based MDFF method. Cross-validated model quality statistics correlated with model accuracy over the three test systems. (Nature Methods, vol. 12, p. 361, 2015).

Cyrus’ CSO Yifan Song uses electrostatics computation to understand ion pump mechanisms

PNAS_400x400

Changing a few residues can change the function of homologous proteins. The chloride and proton affinity in the inward chloride-pumping halorhodopsin (HR) and outward proton-pumping bacteriorhodopsin (BR) are compared using classical electrostatic simulations. BR binds and releases protons from acidic residues that have been removed from HR. In the states where these acids are ionized in BR, HR binds a chloride. In the states where these acids bind a proton in BR, HR releases the chloride. Thus, BR uses static anions and mobile protons, whereas HR uses mobile ions to maintain the same charge states. The use of mobile ions makes HR more sensitive to external conditions.

Full Text Article in PNAS