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Mike Harms

Assistant Professor — of Chemistry and Biochemistry

Member, Institute of Molecular Biology

Lab Website

B.S., Oregon State University, 2004. Ph.D. Johns Hopkins University, 2008. Postdoctoral: Postdoctoral: University of Oregon (2009-2013; Joe Thornton). At Oregon since 2013.



Research Interests:

The overarching goal of the Harms lab is to understand the relationship between the biophysical properties of proteins and their evolution. Why do proteins with certain sequences and physical properties—out of a huge space of possibilities—occur? How do the physical properties of proteins shape their evolutionary trajectories? Which protein features are optimized by evolution, and which are determined by chance? How does a blind evolutionary process assemble complex features like ligand binding sites or allosteric regulation? Is protein evolution predictable or stochastic? To answer these (and other) questions, we take a synthetic approach, combining concepts and methodologies from classical biophysics and evolutionary biology. We employ advanced phylogenetics techniques (including ancestral protein resurrection), high-throughput experimental screens, and rigorous experimental/computational biophysical approaches to directly study the interplay of evolutionary and biophysical forces in generating both the complexity and diversity of natural proteins.

Exploring sequence space

Sequence space provides a rich metaphor to organize thinking about the evolution of proteins and reveal the common ground shared by evolutionary biology and biophysics. The simplest sequence space is a “genotype space” that contains all possible amino acid sequences and the mutational connections between them. Each sequence is a node, and each node is connected by edges to all neighboring proteins that differ from it by just one amino acid. The genotype space becomes a “genotype-phenotype” space when each node is assigned information about its functions. Finally, as they evolve, proteins follow trajectories along edges through the genotype-phenotype space. Biophysics and evolutionary biology have traditionally addressed different aspects of this map. Biophysicists have sought to characterize the map’s structure and its physical determinants —the links among protein sequence, biophysical properties, and function. Evolutionary biologists have studied the trajectories that proteins follow through this map and the evolutionary forces that drive them to do so. We unite these approaches, seeking to reveal how and why proteins evolve across genotype-phenotype space to produce the diversity of proteins found in nature.

The S100 protein family as an evolutionary biophysical model

A powerful model system allows deep and nuanced studies that provide insights inaccessible in more complex systems: Drosophila for evolutionary developmental biology, ribonuclease H for protein folding, and—in our case—the S100 family for evolutionary biophysics. The S100s are small (~10 kDa) allosteric calcium binding proteins that ligate calcium and then recruit and regulate specific target proteins. They possess a number of properties that make them an excellent family for asking evolutionary biophysical questions.

Biophysics and evolutionary biology have traditionally addressed different aspects of this map. Biophysicists have sought to characterize the map’s structure and its physical determinants —the links among protein sequence, biophysical properties, and function. Evolutionary biologists have studied the trajectories that proteins follow through this map and the evolutionary forces that drive them to do so. We unite these approaches, seeking to reveal how and why proteins evolve across genotype-phenotype space to produce the diversity of proteins found in nature.

Figure 1. Sequence space. The left panel shows a simple genotype space. Each possible sequence is a node. Neighboring nodes that differ by only one point mutation are connected by edges. The example shows a three-site protein with only two possible states (0 or 1). The middle panel shows genotype-phenotype space, where each sequence is associated with its functional characteristics, which are determined by the molecule’s biochemical properties. Here, three possible states are shown: function α (orange), function β (blue), and non-functional (gray). An intermediate state between α and β is shown in light blue. Evolutionary processes drive proteins across the genotype-phenotype space. The right panel shows one trajectory beginning at genotype 000 and ending at 111

The S100 protein family as an evolutionary biophysical model

A powerful model system allows deep and nuanced studies that provide insights inaccessible in more complex systems: Drosophila for evolutionary developmental biology, ribonuclease H for protein folding, and—in our case—the S100 family for evolutionary biophysics. The S100s are small (~10 kDa) allosteric calcium binding proteins that ligate calcium and then recruit and regulate specific target proteins. They possess a number of properties that make them an excellent family for asking evolutionary biophysical questions.

Methodology

We employ a variety of methods to explore protein sequence space and study the interplay between its properties and the historical evolutionary process.

Conclusion

The why of proteins lies in the interplay of historical and physical causes, and only a mode of explanation that incorporates both types of analysis can provide a complete understanding of that interplay. By employing a wide variety of phylogenetic, experimental, and computational techniques, members of the Harms lab are working to define the physical determinants of the space over which sequences evolve and characterize the evolutionary processes that produce proteins’ diverse physical properties. Ultimately, we aim to transcend interdisciplinary barriers and treat proteins as integrated physical and historical wholes.

Selected Publications:

Google Scholar Profile

For up-to-date publication list, see lab website.

Harms MJ, Thornton JW. “Evolutionary biochemistry: Revealing the historical and physical causes of protein function.” In press, Nature Reviews Genetics.

Harms MJ, Eick GN, Colucci J, Ortlund EA, Thornton JW. “Biophysical mechanisms for large-effect mutations in the evolution of steroid hormone receptors.” In press, Proceedings of the National Academy of Sciences, USA.

Williams SG, Harms MJ, Hall KB. “Resurrection of an Urbilaterian U1A/U2B’’/SNF protein.” In press, Journal of Molecular Biology.

Eick GN, Colucci J, Harms MJ, Ortlund EA, Thornton JW. “Evolution of minimal specificity in the steroid receptors.” (2012) PLoS Genetics. 8(11):e1003072.

Harms MJ, Schlessman JL, Sue GR, García-Moreno E. B. “Arginine is ionized at internal positions in a protein.” Proceedings of the National Academy of Sciences, USA. 108(47):18954-9 (“Must read” on Faculty of 1000).

Bridgham JT, Eick G, Larroux C, Deshpande K, Harms MJ, Gauthier MEA, Ortlund EA, Degnan BM, Thornton JW (2010). “Protein evolution by molecular tinkering: diversification of the nuclear receptor superfamily from a ligand-dependent ancestor.” PLoS Biology 8(10): e1000497.

Harms MJ, Thornton JW. (2010). “Analyzing protein structure and function using ancestral gene reconstruction.” Current Opinions in Structural Biology. 20(3):360-366.

Harms MJ, Castañeda CA, Schlessman JL, Sue GR, Isom DG, Cannon BR, García-Moreno E. B. (2009). “The pKa values of acidic and basic residues buried at the same internal location in a protein are governed by different factors.” Journal of Molecular Biology. 389:34-47 (“Must read” on Faculty of 1000).

Harms MJ, Schlessman JL, Chimenti MS, Sue GR, Damjanovic A, García-Moreno E. B. (2008). “A buried lysine that titrates with a normal pKa: Role of conformational flexibility at the protein–water interface as a determinant of pKa values.” Protein Science. 17:833-845.

Hays FA, Teegarden A, Jones ZJR, Harms MJ, Raup D, Watson F, Cavaliere E, Ho PS. (2005). “How sequence defines structure: a crystallographic map of DNA structure and conformation.” Proceedings of the National Academy of Sciences USA. 102(20):7157-7162.

Harms MJ, Wilmarth PA, Kapfer DM, Steel EA, David LL, Bachinger HP, Lampi KJ. (2003). “Laser light-scattering evidence for an altered association of βB1-crystallin deamidated in the connecting peptide.” Protein Science. 13:678-686.

To Contact Dr. Harms:
Phone: 541-346-1537
harms@molbio.uoregon.edu