Positive and Negative Design in Stability and Thermal Adaptation of Natural Proteins

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Positive and Negative Design in Stability and Thermal Adaptation of Natural Proteins

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Title: Positive and Negative Design in Stability and Thermal Adaptation of Natural Proteins
Author: Shakhnovich, Eugene; Zeldovich, Konstantin B.; Berezovsky, Igor N.

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Citation: Berezovsky, Igor N., Konstantin B. Zeldovich, and Eugene I. Shakhnovich. 2007. Positive and negative design in stability and thermal adaptation of natural proteins. PLoS Computational Biology 3, no. 3: 0498-0507.
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Abstract: The aim of this work is to elucidate how physical principles of protein design are reflected in natural sequences that evolved in response to the thermal conditions of the environment. Using an exactly solvable lattice model, we design sequences with selected thermal properties. Compositional analysis of designed model sequences and natural proteomes reveals a specific trend in amino acid compositions in response to the requirement of stability at elevated environmental temperature: the increase of fractions of hydrophobic and charged amino acid residues at the expense of polar ones. We show that this “from both ends of the hydrophobicity scale” trend is due to positive (to stabilize the native state) and negative (to destabilize misfolded states) components of protein design. Negative design strengthens specific repulsive non-native interactions that appear in misfolded structures. A pressure to preserve specific repulsive interactions in non-native conformations may result in correlated mutations between amino acids that are far apart in the native state but may be in contact in misfolded conformations. Such correlated mutations are indeed found in TIM barrel and other proteins.
Published Version: http://dx.doi.org/10.1371/journal.pcbi.0030052
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:2624673

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  • FAS Scholarly Articles [7106]
    Peer reviewed scholarly articles from the Faculty of Arts and Sciences of Harvard University
 
 

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