Evolutionary biochemistry: revealing the historical and physical causes of protein properties

Key Points

  • Evolutionary biochemistry aims to dissect the evolutionary processes and physical mechanisms by which biological molecules diversified and to reveal how their physical architecture facilitates and constrains their evolution.

  • The historical separation between biochemists and evolutionary biologists is breaking down, allowing for powerful investigations of protein evolution at the interface of the two disciplines.

  • Among the key techniques for studying the biochemical mechanisms of protein evolution are ancestral protein reconstruction, directed laboratory evolution and high-throughput evolutionary analysis of protein sequence space.

  • Evolutionary analysis illuminates core questions in biochemistry because it can efficiently reveal the sequence determinants of differences in function, structure and other physical properties among proteins. It also provides the ultimate explanation for why any protein has the properties it has today.

  • Biochemical approaches illuminate core questions in molecular evolution because they can reveal the mechanisms by which historical mutations led to the emergence of new phenotypes, they can characterize the topology of the genotype–function space on which evolution occurred, and they can illuminate how the physical properties of biological molecules shaped the evolutionary processes.

  • Work in evolutionary biochemistry explains the interplay of contingency and determinism in molecular evolution as the result of the specific functional constraints and genetic interactions that are produced by the physical architecture of each protein.

Abstract

The repertoire of proteins and nucleic acids in the living world is determined by evolution; their properties are determined by the laws of physics and chemistry. Explanations of these two kinds of causality — the purviews of evolutionary biology and biochemistry, respectively — are typically pursued in isolation, but many fundamental questions fall squarely at the interface of fields. Here we articulate the paradigm of evolutionary biochemistry, which aims to dissect the physical mechanisms and evolutionary processes by which biological molecules diversified and to reveal how their physical architecture facilitates and constrains their evolution. We show how an integration of evolution with biochemistry moves us towards a more complete understanding of why biological molecules have the properties that they do.

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Figure 1: Parallel evolution due to biophysical constraints.
Figure 2: Molecular mechanisms of evolutionary epistasis.
Figure 3: The position of a protein in its neutral network determines which mutational path it takes to a derived function.

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Acknowledgements

This work was supported by US National Institutes of Health Grants R01-GM081592, R01-GM104397 and F32-GM090650, as well as by the Howard Hughes Medical Institute. The authors thank A. Drummond, T. Dean and members of the Thornton laboratory for helpful comments.

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Correspondence to Joseph W. Thornton.

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Glossary

Biochemistry

The study of the chemical and physical properties of biological molecules and how those properties determine the functions of each molecule. Defined this way, biochemistry also includes structural biology, biophysics and some areas of molecular and computational biology.

Molecular clock

The hypothesis that, over long timescales, mutations accumulate at a characteristic rate for each gene. For genes with clock-like evolution, the proportion of sequence differences between related genes can be used to estimate the time since they diverged.

Ancestral protein reconstruction

The use of statistical phylogenetic methods to infer ancestral protein sequences from large alignments of present-day proteins, followed by synthesis, expression and experimental characterization of the 'resurrected' ancestral proteins.

Homology

Similarity due to descent from a shared common ancestral form.

Protein stability

A thermodynamic description of the difference in free energy between the folded and unfolded states of a protein.

Parallel evolution

The repeated acquisition of the same phenotype on different lineages under similar forms of selection.

Epistasis

Dependency of the phenotypic effects of a mutation on the genetic state at other sites in the same or other loci.

Sequence signatures

Patterns in groups of protein or DNA sequences — such as the relative frequency of synonymous and nonsynonymous mutations or the degree of genetic diversity within and between populations — that are interpreted as reflecting specific evolutionary processes.

Directed evolution

A laboratory procedure for identifying genotypes with a desired property by iteratively introducing random mutations into a protein and using chemical or biological means to select for variants in which the property is improved.

Mutation–selection balance

Equilibrium between the accumulation of variation in a population due to ongoing mutation and the removal of variation due to purifying selection.

Genetic drift

Changes in the frequency across generations of genotypes in populations due to stochastic factors.

Neutral network

A set of protein sequences that are connected to each other by single amino acid replacements and have similar enough functions and physical properties that selection does not distinguish among them.

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Harms, M., Thornton, J. Evolutionary biochemistry: revealing the historical and physical causes of protein properties. Nat Rev Genet 14, 559–571 (2013). https://doi.org/10.1038/nrg3540

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