Using computer simulations, University of Oregon researchers find that knowing all possible mutations isn't enough to predict where a protein will go
University of Oregon scientists theorized that they could manipulate a protein one mutation at a time and predict its evolution. They sought to prove it. And failed.
Researchers in the University of Oregon lab of Michael Harms predicted the evolutionary paths of different simulated proteins. The points in the image are protein sequences. The edges denote probabilities of trajectories. Colors denote low to high fitness (purple to yellow) or falsely inaccessible or falsely accessible routes (red and blue).
Illustration by Michael Harms and Zach Sailer
They do think, however, that they've found a fundamental truth underlying unpredictability in a biological system. Basic physical limitations make uncertainty the norm, they reported in a paper published online Oct. 23 in the Proceedings of the National Academy of Sciences.
"While we got a surprising negative result, we were able to say why," said Michael J. Harms, a professor in the UO Department of Chemistry and Biochemistry and scientist in the Institute of Molecular Biology. "That is a positive. Our simple study provides confirmation of what many people in the field have observed repeatedly -- unpredictability. It appears it is universal."
The research was a digital affair, done with computer simulations designed by UO doctoral student Zachary R. Sailer. He and Harms created a simple lattice protein, using an approach previously created in the Harms lab, with a random sequence of 12 amino acids. They then ran evolutionary simulations to optimize stability, a physical property of the protein.
The goal was to use the effects of all 228 mutations known to be associated with the starting protein to predict these simulated trajectories: which mutation would occur, when, over time. The ability to project ahead faded fast after the first two mutations. After that, the anticipated trajectories went astray amid a growing number of rerouting probabilities.
"The quality of your information actually decays over time," Sailer said. "As mutations accumulate, the effects of the mutations that you measured start to change so that you can't predict where you are going."
In their paper, Sailer and Harms suggest that physics, particularly thermodynamics, is at play. Each mutation alters the protein in a small, but nonlinear way. This means that the effect of each mutation depends on all mutations that occurred before.
"I think that what we showed, fundamentally, is that even if you know a lot about a system, about a protein, you cannot predict how it evolves because of the physics of the system," Harms said. "There are physical rules that limit evolution and its predictability."
How proteins evolve is a fundamental question in evolutionary biology, from both a philosophical perspective, to learn more about the machinery of biological systems, and for clues that might lead to improved or better drugs.
"Practically," Harms said, "our research may help us learn how to prevent the evolution of antibiotic resistance in bacteria." Almost all bacterial borne infections are developing resistance to antibiotics, creating a leading public health concern around the world.
"Rather than studying the effects of all individual mutations," Sailer added, "maybe we should study random combinations of many mutations. Such an approach might help us predict the evolution of resistance."
Work is underway in the Harms lab to test for this possibility on real proteins. "We're building computational tools that let us analyze antibiotic resistance datasets, and we are getting hints that a combinatorial approach does work," Harms said. "It's more complicated than studying individual mutations, but our work shows the individual approach is unlikely to work."
A fellowship to Harms from the Alfred P. Sloan Foundation funded the research. The UO also provided additional research funds to Sailer.
Sources: Michael J. Harms, assistant professor, Department of Chemistry and Biochemistry and Institute of Molecular Biology, 541-346-9002, email@example.com, and Zachary R. Sailer, doctoral student, Department of Chemistry and Biochemistry and Institute of Molecular Biology, 541-346-9003, firstname.lastname@example.org
Note: The UO is equipped with an on-campus television studio with a point-of-origin Vyvx connection, which provides broadcast-quality video to networks worldwide via fiber optic network. There also is video access to satellite uplink and audio access to an ISDN codec for broadcast-quality radio interviews.
About Michael Harms: http://molbio.
Harm's Lab: https:/
Institute of Molecular Biology: http://molbio.
Department of Chemistry and Biochemistry: https:/
Jim Barlow | EurekAlert!
One step closer to reality
20.04.2018 | Max-Planck-Institut für Entwicklungsbiologie
The dark side of cichlid fish: from cannibal to caregiver
20.04.2018 | Veterinärmedizinische Universität Wien
University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.
Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.
Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.
Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...
Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.
The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...
Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.
Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...
In the fight against cancer, scientists are developing new drugs to hit tumor cells at so far unused weak points. Such a “sore spot” is the protein complex...
13.04.2018 | Event News
12.04.2018 | Event News
09.04.2018 | Event News
20.04.2018 | Physics and Astronomy
20.04.2018 | Physics and Astronomy
20.04.2018 | Physics and Astronomy