An evolutionary approach outperforms a design approach in modeling protein sequence variation.

Over generations, evolution shapes proteins, leading to variation in their amino acid sequences both between and within species. Despite our ever-increasing knowledge of the physical constraints that guide protein structure, advanced modeling techniques don’t capture the site-specific variability observed in natural proteins. Bafflingly, complex models that account for physical influences on the positions of all atoms in a protein often perform worse than elementary models at recapitulating natural proteins’ variability.

In GENETICS, Jiang, Teufel, et al. provide evidence for a possible explanation: advanced modeling techniques don’t take into account the order of the steps by which protein sequences change. A popular protein-design suite called RosettaDesign, for example, deletes the amino acid side chains from a template structure, leaving only the peptide backbone, and then replaces them with new side chains all at once. After this dramatic step, additional changes are made to maximize the protein’s calculated stability.

Evolution works very differently. Sequence changes are usually made one amino acid residue at a time, meaning the effect of each alteration depends on how it fits with the existing sequence. Whether a sequence change will be fixed or lost depends on how it affects fitness, which is partly influenced by how it impacts protein stability—variations that make proteins prone to unfolding are typically not favorable.

When the group tested their new algorithm, which functions more similarly to evolution, on the same natural proteins, they found that its effects were different in several ways from those of RosettaDesign. In almost every case, their evolved sequences resembled natural ones more than designed proteins’ sequences did. This might not, at first, seem surprising, since the designed proteins started with a completely stripped peptide backbone and thus shouldn’t have been influenced as much by the natural starting sequences—but the researchers found that this wasn’t the reason. Even when they used a designed sequence as a template, the evolution-based simulation created sequences that better mimicked natural ones.

In protein design, the ability to build proteins with sequences unlike natural ones could be interpreted as a positive thing since it’s conceivable that these proteins would have a wider range of properties than those of proteins found in the wild. But despite the fact that the designed sequences had diverged more from the starting sequences, their site-specific variability was lower than that of the evolved sequences. This implies that, even though a greater number of sites were altered in the designed sequences, the changes were restricted to a smaller set of amino acid residues.

RosettaDesign and similarly sophisticated software have facilitated major advances in protein design, such as developing new enzymes and previously unseen protein folds, and Jiang, Tuefel, et al.’s findings don’t make these types of software obsolete. Different computational techniques fill different niches, and they evolve just as proteins do, with new variants continuously under development. By tweaking existing methods and studying the effects of new algorithms, we can improve how we use these techniques—and perhaps develop new ones with even better fitness than their ancestors had.

CITATION:

Beyond Thermodynamic Constraints: Evolutionary Sampling Generates Realistic Protein Sequence Variation
Qian Jiang, Ashley I. Teufel, Eleisha L. Jackson, Claus O. Wilke
GENETICS 2018 208: 1387-1395; https://doi.org/10.1534/genetics.118.300699
http://www.genetics.org/content/208/4/1387

 

[wysija_form id=”1″]

, ,

Nicole Haloupek is a freelance science writer and a recent graduate of UC Berkeley's molecular and cell biology PhD program.

View all posts by Nicole Haloupek »

Read more in

  • Ed Grell at his dissecting microscope using ether to anesthetize his flies.

    In Memoriam: Ellsworth Herman Grell (1932–2023), a pioneer of Drosophila genome engineering and annotation

    Ellsworth (Ed) Grell blessed the Drosophila community through three enduring legacies: as a pioneer of chromosome mechanics, as a primary organizer and synthesizer of genetic knowledge in Drosophila, and as a graceful mentor to those fortunate to have known him personally. Ed grew up in rural Nebraska, completed his undergraduate studies at Iowa State, and…

  • Congratulations to the #Fungal24 Poster Award winners!

    We are pleased to announce the recipients of the GSA Poster Awards for posters presented at the 32nd Fungal Genetics Conference! Undergraduate and graduate student members of GSA were eligible for the awards, and a hard-working team of judges made the determinations. Congratulations to all! Felicia Ebot Ojong, The University of Georgia My research is focused…

  • Poster presentation tips for TAGC 2024

    You’ve been selected to present a poster at The Allied Genetics Conference 2024 in March—you’ve celebrated, made plans to attend, now what? This is an exciting opportunity to showcase your research and engage with fellow members of the genetics community, so you want to make sure you’re prepared. We wanted to offer you some tips…

  • Maximize your TAGC 2024 experience 

    A guide to all that National Harbor & DC have to offer Are you joining us for The Allied Genetics Conference 2024 in March? Make the most of your #TAGC24 experience in National Harbor! We know the science will keep you busy, but you deserve to unwind and have some fun, so we’ve curated a…

  • Early Career Leadership Spotlight: Sarah Petrosky

    We’re taking time to get to know the members of the GSA’s Early Career Scientist Committees. Join us to learn more about our early career scientist advocates. Sarah PetroskyMultimedia SubcommitteeUniversity of Pittsburgh Research Interest I am interested in understanding adaptation that has been happening recently in populations by dissecting the ways that genes underlying an adaptation…

  • TAGC 2024 Early Career Award Winners

    GSA is pleased to announce the winners of the early career awards presented at The Allied Genetics Conference 2024. These awards are specific to particular TAGC communities and recognize early career scientists’ outstanding work on their respective research organisms. The awardees will present their talks in keynote sessions at TAGC 2024.  Don’t miss the opportunity…

  • Preeminent geneticists recognized with revamped GSA Awards

    In 2022, GSA’s Board of Directors launched an audit to review the five major awards conferred by the Society. Today, we are thrilled to announce the recipients of the reimagined GSA Awards, including the new Genetics Society of America Early Career Medal. The scientists honored this year are recognized by their peers for their outstanding…

  • Fly Board funds outreach programs to spread the word about Drosophila research

    In 2020, the Fly Board voted to use part of its reserve fund to support efforts to increase trainee participation as well as equity and diversity in the Drosophila community. An awards committee decides how the money will be spent each year, and from 2020–2022, the committee posted a very broad call for applications from…

  • New members of the GSA Board of Directors: 2024–2026

    We are pleased to announce the election of four new leaders to the GSA Board of Directors: 2024 Vice President/2025 President Brenda Andrews Professor, University of Toronto It’s an honor to continue my association with the Society by serving as Vice President of the Board of Directors. I have broad knowledge of the ongoing activities…

  • A rose-ringed parakeet, one of three parrot species used in the study.

    Parrot plumage study aids breeders and endangered natural populations

    Yellow coloration is maladaptive in the wild but prized by breeders. People have long been fascinated with birds, which exhibit one of the widest ranges of coloration among vertebrates. Parrots, in particular, have captivated humans by their ability to mimic human speech and spectacular plumage. Brightly colored feathers are used primarily to attract mates, intimidate…

  • Early Career Leadership Spotlight: Sarah Gilmour

    We’re taking time to get to know the members of the GSA’s Early Career Scientist Committees. Join us to learn more about our early career scientist advocates. Sarah GilmourMultimedia SubcommitteeStowers Institute for Medical Research Research Interest Questions of evolution have always fascinated me. I am extremely fortunate to be starting out my research career in a…