The spatial architecture of protein function and adaptation

McLaughlin, Richard N.; Poelwijk, Frank J.; Raman, Arjun S.; Gosal, Walraj S.; Ranganathan, Rama

doi:10.1038/nature11500

Cited by 450 publications

(614 citation statements)

References 35 publications

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“…Although the formal validity of their inference has been the topic of debate (91), our simulation results are in accordance with their basic contention and provide a detailed view of the form of epistasis in proteins under purifying selection. Our results are also consistent with the results of both theoretical (60) and empirical studies (6,72) showing that epistatic interactions are in large part governed by underlying biophysical interactions between substitutions.…”

Section: Discussionsupporting

confidence: 91%

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Contingency and entrenchment in protein evolution under purifying selection

Shah

McCandlish

Plotkin

2015

Proc. Natl. Acad. Sci. U.S.A.

183

236

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The phenotypic effect of an allele at one genetic site may depend on alleles at other sites, a phenomenon known as epistasis. Epistasis can profoundly influence the process of evolution in populations and shape the patterns of protein divergence across species. Whereas epistasis between adaptive substitutions has been studied extensively, relatively little is known about epistasis under purifying selection. Here we use computational models of thermodynamic stability in a ligand-binding protein to explore the structure of epistasis in simulations of protein sequence evolution. Even though the predicted effects on stability of random mutations are almost completely additive, the mutations that fix under purifying selection are enriched for epistasis. In particular, the mutations that fix are contingent on previous substitutions: Although nearly neutral at their time of fixation, these mutations would be deleterious in the absence of preceding substitutions. Conversely, substitutions under purifying selection are subsequently entrenched by epistasis with later substitutions: They become increasingly deleterious to revert over time. Our results imply that, even under purifying selection, protein sequence evolution is often contingent on history and so it cannot be predicted by the phenotypic effects of mutations assayed in the ancestral background.intragenic epistasis | coevolution | near neutrality | protein stability W hether a heritable mutation is advantageous or deleterious to an organism often depends on the evolutionary history of the population. A mutation that is beneficial at the time of its introduction may confer its beneficial effect only in the presence of other potentiating or permissive mutations (1-9). Thus, the fate of a mutation arising in a population may be contingent on previous mutations (10-13). Conversely, once a mutation has fixed in a population, the mutation becomes part of the genetic background onto which subsequent modifications are introduced. Because the beneficial effects of the subsequent modifications may depend on the focal mutation, as time passes reversion of the focal mutation may become increasingly deleterious, leading to a type of evolutionary conservatism, or entrenchment (14-18).In the context of protein evolution, the effects of contingency and entrenchment are most easily studied by considering a sequence of single amino acid changes (19) that extends both forward and backward in time from some focal substitution. To assess the roles of contingency and entrenchment we can study the degree to which each focal substitution was facilitated by previous substitutions, and the degree to which the focal substitution influences the subsequent course of evolution (Fig. 1A).Dependencies within a sequence of substitutions are closely connected to the concept of epistasis-that is, the idea that the phenotypic effect of a mutation at a particular genetic site may depend on the genetic background in which it arises (20-24). In the absence of epistasis, a mutation has the same effect ...

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Section: Discussionsupporting

confidence: 91%

“…A mutation that is beneficial at the time of its introduction may confer its beneficial effect only in the presence of other potentiating or permissive mutations (1)(2)(3)(4)(5)(6)(7)(8)(9). Thus, the fate of a mutation arising in a population may be contingent on previous mutations (10)(11)(12)(13).…”

mentioning

confidence: 99%

Contingency and entrenchment in protein evolution under purifying selection

Shah

McCandlish

Plotkin

2015

Proc. Natl. Acad. Sci. U.S.A.

183

236

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“…Often, the activity of the main functional site depends on the binding of an effector on a distant site (1,2). Such an allosteric behavior can occur over large distances, such as 20 residues or more (3), and often involves only a sparse subset of residues in the protein (3,4). Allosteric regulation offers an appealing target for drug design (5), and there is considerable interest in predicting allosteric pathways (6,7).…”

mentioning

confidence: 99%

“…One central difficulty is that the physical mechanisms allowing such an "action at a distance" remain elusive. In some cases, allostery can be understood as the modulation of a hinge connecting two extended rigid parts of the protein (8,9), but, often, the displacement field induced by the binding of the effector cannot be described in these terms (4,10,11). Another route, statistical coupling analysis (12), considers correlations within sequences of proteins of the same family to infer allosteric pathways (4,7).…”

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confidence: 99%

Architecture and coevolution of allosteric materials

Yan

Ravasio

Brito

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

123

138

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We introduce a numerical scheme to evolve functional elastic materials that can accomplish a specified mechanical task. In this scheme, the number of solutions, their spatial architectures, and the correlations among them can be computed. As an example, we consider an "allosteric" task, which requires the material to respond specifically to a stimulus at a distant active site. We find that functioning materials evolve a less-constrained trumpetshaped region connecting the stimulus and active sites, and that the amplitude of the elastic response varies nonmonotonically along the trumpet. As previously shown for some proteins, we find that correlations appearing during evolution alone are sufficient to identify key aspects of this design. Finally, we show that the success of this architecture stems from the emergence of soft edge modes recently found to appear near the surface of marginally connected materials. Overall, our in silico evolution experiment offers a window to study the relationship between structure, function, and correlations emerging during evolution. disordered materials | proteins | evolution P roteins are long polymers that can fold in a reproducible way and achieve a specific function. Often, the activity of the main functional site depends on the binding of an effector on a distant site (1, 2). Such an allosteric behavior can occur over large distances, such as 20 residues or more (3), and often involves only a sparse subset of residues in the protein (3, 4). Allosteric regulation offers an appealing target for drug design (5), and there is considerable interest in predicting allosteric pathways (6, 7). One central difficulty is that the physical mechanisms allowing such an "action at a distance" remain elusive. In some cases, allostery can be understood as the modulation of a hinge connecting two extended rigid parts of the protein (8, 9), but, often, the displacement field induced by the binding of the effector cannot be described in these terms (4, 10, 11). Another route, statistical coupling analysis (12), considers correlations within sequences of proteins of the same family to infer allosteric pathways (4, 7). The generality of this elegant approach is, however, debated (13).From a physical viewpoint, specific response at a distance is surprising. The structure of proteins is similar to randomly packed spheres (14). Generically, the response of such systems is nonspecific and decays rapidly in space (in a manner similar to a continuum medium) at distances larger than the particle size; this is true, except close to a critical point where the number of constraints coming from strongly interacting particles is just sufficient to match the number of degrees of freedom of the particles (15). There, the elastic response becomes heterogeneous on all scales (16,17). This point is illustrated in Fig. 1A, showing the rapidly decaying response of a random spring network to a stimulus. However, as shown in Fig. 1B (and independently found in ref. 18 using a different algorithm), springs can be move...

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“…Nevertheless, the protein is not a monolith: its dynamic nature means that under certain conditions the packing of polypeptide chains may undergo relaxation, enabling small molecules to penetrate protein interior [1][2][3][4][5][6]. Those ligands cannot form stable bonds due to low binding energy in an area otherwise unprepared for specific interaction with such compounds -to put it simply, a rigid molecule is not likely to exhibit good alignment with the conformation of a folded polypeptide chain.…”

mentioning

confidence: 99%

Supramolecular Systems as Protein Ligands

Rybarska

Piekarska

Stopa

et al. 2017

Self-Assembled Molecules – New Kind of Protein Ligands

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The standard substrate complexation mechanism engages natural binding sites. In contrast, supramolecular structures may form complexes with proteins by penetrating in regions which are either naturally unstable or become temporarily accessible due to structural rearrangements related to the protein's function. This may result in enhancement of irreversible processes (e.g. immune complexation or complement activation) or inhibition of reversible processes (e.g. enzymatic catalysis). Only ribbon-like supramolecular structures may form complexes with proteins. Having anchored itself inside the protein, the supramolecular ligand is protected against environmental factors such as changes in pH. This type of interaction represents a unique, nonstandard phenomenon in the context of proteomics.

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The spatial architecture of protein function and adaptation

Cited by 450 publications

References 35 publications

Contingency and entrenchment in protein evolution under purifying selection

Contingency and entrenchment in protein evolution under purifying selection

Architecture and coevolution of allosteric materials

Supramolecular Systems as Protein Ligands

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