Thermodynamic prediction of protein neutrality.

By Jesse D. Bloom, Jonathan J Silberg, Claus O. Wilke, D. A. Drummond, Christoph Adami, Frances H. Arnold, Alan R. Fersht, Brian K. Shoichet. 2004

215 citations recorded by the source corpus.

We present a simple theory that uses thermodynamic parameters to predict the probability that a protein retains the wild-type structure after one or more random amino acid substitutions. Our theory predicts that for large numbers of substitutions the probability that a protein retains its structure will decline exponentially with the number of substitutions, with the severity of this decline determined by properties of the structure. Our theory also predicts that a protein can gain extra robustness to the first few substitutions by increasing its thermodynamic stability. We validate our theory with simulations on lattice protein models and by showing that it quantitatively predicts previously published experimental measurements on subtilisin and our own measurements on variants of TEM1 beta-lactamase. Our work unifies observations about the clustering of functional proteins in sequence space, and provides a basis for interpreting the response of proteins to substitutions in protein engineering applications.

Subfields: Materials Chemistry, Molecular Biology

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Citations in the corpus

Exploring protein fitness landscapes by directed evolution (2009, positive): “Proteins are in fact robust to mutation — a significant fraction of possible mutants retain their fold and functio”
Relationship between protein thermodynamic constraints and variation of evolutionary rates among sites (2014, methodology): “While this assumption cannot strictly be true, in practice it has worked well in several applications (e.g. Bloom et al. 2005, Bloom & Glassman 2009).”
A structural model of latent evolutionary potentials underlying neutral networks in proteins (2007, methodology): “…models, e.g., regarding connected neutral nets and superfunnels, appear to be robust over a diverse set of different interaction schemes (Govindarajan and Goldstein, 1997; Williams et al., 2001; Wroe et al., 2005), and they are consistent with experiments (Bloom et al., 2005; Cordes et al., 2000).”
Evolvability as a function of purifying selection in TEM-1 β-lactamase. (2015, unknown): “The idea is that the ''extra'' stability beyond that required to asymptotically populate the native state provides a thermodynamic basis for robustness by buffering the slightly destabilizing effects of most mutations (Bloom et al., 2005; Tokuriki and Tawfik, 2009; Wylie and Shakhnovich, 2011).”
Epistasis in protein evolution (2016, unknown): “Similarly, in the antibiotic resistance gene TEM-1 b-lactamase, a “global suppressor” mutation M182T stabilizes the protein, relieving the otherwise deleterious effect of many other mutations that reduce protein stability, including many that enhance the protein’s activity on new antibiotics.(76,78,”
Neutralism and selectionism: a network-based reconciliation (2008, background): “The more robust a molecule is, the more likely it is that mutations in it are neutral, and that they do not change the structure and function of the molecul”
Missense meanderings in sequence space: a biophysical view of protein evolution (2005, unknown): “Our model shares broad similarities with LATTICE MODELS of protein evolutio”
How Protein Stability and New Functions Trade Off (2008, background): “proteins [1–6], but also in engineering, designing, and evolving,”
Inferring the shape of global epistasis (2018, background): “, thermodynamic stability for a protein’s native conformation is almost always and important phenotype, and there is a consistent thread in the literature suggesting that the phenotypic effects of most mutations are mediated via their effects on thermodynamic stability and the non-linear relationshi”
Inferring Stabilizing Mutations from Protein Phylogenies: Application to Influenza Hemagglutinin (2009, unknown): “is that the evolutionary impact of a mutation can depend on the stability of the parent protein into which it is introduced, with a moderately destabilizing mutation being neutral in the context of a stable parent but lethal to a marginally”
Consensus protein design (2016, background): “However, extra thermodynamic stability is known to increase the robustness of the native structure to random mutations by increasing the fraction of variants that continue to possess the minimal stability required to fold (Nikolova et al., 2000; Bloom et al., 2005, 2006).”
Stability effects of mutations and protein evolvability. (2009, unknown): “The computed distributions show remarkable resemblance to distributions of a large dataset of experimental DDG values [14 ,31], and those computed for model lattice proteins [4 ,34].”