Journal of the American Chemical Society · 2006 · 198 citations · 32 references
Life SciencesComputational DesignMolecular BiologyProtein EngineeringProtein FoldingStructural BiologyProtein DesignProtein Design ModelingProtein Fold RecognitionProtein Folding PathwaysProtein StructureProtein Structure ModelingComputational Protein DesignProtein Conformational ChangesProtein Design AlgorithmsProtein Fold DesignReversible Conformational ChangesRotamer Optimization AlgorithmsSimulated AnnealingZinc Finger Motifs
The functions of many proteins depend on specific conformational changes, so designing primary sequences that can adopt multiple secondary and tertiary structures is key to creating novel functional proteins. The authors developed an algorithm that optimizes a single amino acid sequence for multiple target structures. The algorithm employs a Monte Carlo simulated‑annealing outer loop to sample sequence space, while an inner loop evaluates the effect of each mutation on the target structures using RosettaDesign’s rotamer packing and composite energy function. Experimental testing of the peptide Sw2 demonstrates that it can reversibly switch between a 2Cys‑2His zinc‑finger‑like fold and a trimeric coiled‑coil fold depending on pH or the presence of transition metals.
The functions of many proteins are mediated by specific conformational changes, and therefore the ability to design primary sequences capable of secondary and tertiary changes is an important step toward the creation of novel functional proteins. To this end, we have developed an algorithm that can optimize a single amino acid sequence for multiple target structures. The algorithm consists of an outer loop, in which sequence space is sampled by a Monte Carlo search with simulated annealing, and an inner loop, in which the effect of a given mutation is evaluated on the various target structures by using the rotamer packing routine and composite energy function of the protein design software, RosettaDesign. We have experimentally tested the method by designing a peptide, Sw2, which can be switched from a 2Cys-2His zinc finger-like fold to a trimeric coiled-coil fold, depending upon the pH or the presence of transition metals. Physical characterization of Sw2 confirms that it is able to reversibly adopt each intended target fold.
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