This Article Full Text Full Text (PDF) All Versions of this Article: biophysj.104.050369v1 88/1/118    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wroe, R. Articles by Chan, H. S. Search for Related Content PubMed PubMed Citation Articles by Wroe, R. Articles by Chan, H. S.

Comparing Folding Codes in Simple Heteropolymer Models of Protein Evolutionary Landscape: Robustness of the Superfunnel Paradigm

Richard Wroe ^*, Erich Bornberg-Bauer  and Hue Sun Chan 

^* Faculty of Life Sciences, University of Manchester, United Kingdom; Bioinformatics Division, School of Biological Sciences, University of Münster, Münster, Germany; and Protein Engineering Network of Centres of Excellence, Department of Biochemistry, and Department of Medical Genetics and Microbiology, Faculty of Medicine, University of Toronto, Ontario, Canada

Correspondence: Address reprint requests to Hue Sun Chan, Protein Engineering Network Centres of Excellence, Dept. of Biochemistry and Dept. of Medical Genetics and Microbiology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Tel.: 1-416-978-2697; Fax: 1-416-978-8548, E-mail: chan{at}arrhenius.med.toronto.edu.

Understanding the evolution of biopolymers is a key element in rationalizing their structures and functions. Simple exact models (SEMs) are well-positioned to address general principles of evolution as they permit the exhaustive enumeration of both sequence and structure (conformational) spaces. The physics-based models of the complete mapping between genotypes and phenotypes afforded by SEMs have proven valuable for gaining insight into how adaptation and selection operate among large collections of sequences and structures. This study compares the properties of evolutionary landscapes of a variety of SEMs to delineate robust predictions and possible model-specific artifacts. Among the models studied, the ruggedness of evolutionary landscape is significantly model-dependent; those derived from more proteinlike models appear to be smoother. We found that a common practice of restricting protein structure space to maximally compact lattice conformations results in (i.e., "designs in") many encodable (designable) structures that are not otherwise encodable in the corresponding unrestrained structure space. This discrepancy is especially severe for model potentials that seek to mimic the major role of hydrophobic interactions in protein folding. In general, restricting conformations to be maximally compact leads to larger changes in the model genotype-phenotype mapping than a moderate shifting of reference state energy of the model potential function to allow for more specific encoding via the "designing out" effects of repulsive interactions. Despite these variations, the superfunnel paradigm applies to all SEMs we have tested: For a majority of neutral nets across different models, there exists a funnel-like organization of native stabilities for the sequences in a neutral net encoding for the same structure, and the thermodynamically most stable sequence is also the most robust against mutation.

This article has been cited by other articles:

				J. D. Bloom, D. A. Drummond, F. H. Arnold, and C. O. Wilke Structural Determinants of the Rate of Protein Evolution in Yeast Mol. Biol. Evol., September 1, 2006; 23(9): 1751 - 1761. [Abstract] [Full Text] [PDF]

				T. Aynechi and I. D. Kuntz An Information Theoretic Approach to Macromolecular Modeling: I. Sequence Alignments Biophys. J., November 1, 2005; 89(5): 2998 - 3007. [Abstract] [Full Text] [PDF]