Science for Health
29 May 2012
NIMR and University of Colorado scientists have discovered that proteins predictably adjust through coevolutionary processes when an amino acid is replaced. The research is published in Proceedings of the National Academy of Sciences, USA.
Molecular evolution studies seek to understand the patterns of evolutionary change at different positions in a biological macromolecule. Understanding these changes and how they respond to details of structure and function can help us to better decode the evolutionary record and construct more accurate phylogenies. It can also improve our ability to predict important features of protein structure and function. Key questions concern how evolutionary processes vary among sites and over time, and how the evolution at different locations influences each other.
It has been observed that replacements of amino acids in a protein are more frequent among amino acids with similar physicochemical properties. In other words, changes are more likely to occur if they are conservative with respect to the properties of the previous resident amino acid. It is also known that the important properties of proteins (e.g., structure, function, and stability) are holistic and depend on interactions between amino acids. Hence, as different locations undergo substitutions, the interactions with other sites will change.
NIMR scientists Grant Thiltgen and Richard Goldstein (pictured), along with David Pollock of the University of Colorado (formerly at the NIMR), used simulations of purple acid phosphatase evolution to show that amino acid propensities at a position undergo predictable change after an amino acid replacement at that position. After a replacement, the new amino acid and similar amino acids tend to become gradually more acceptable over time at that position. In other words, proteins tend to equilibrate to the presence of an amino acid at a position through replacements at other positions.
Our most notable finding is the existence of what we call an evolutionary Stokes shift. This means that proteins will tend to adjust to having a particular amino acid at a position. They do this by coevolving, or changing the amino acid sequences at other amino acid positions in response to the particular amino acid at the first position. Hence, over time the inherent propensity for an amino acid at a position will be, on average, higher than it was when the amino acid was first replaced at that position. Not only that, but similar amino acids will tend to have higher propensity as well. These observations are related to the insights of both Sir George Stokes, one of the founders of fluid dynamics, optics and mathematical physics, and Sir Ronald Fisher, one of the founders of mathematical population genetics and statistics.
These results have profound implications for the study of protein evolution and the modeling of evolutionary processes. We will have to re-think the assumptions we used to make and how we go about these things.
RIchard Goldstein & David Pollock
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Average propensity of the resident amino acid at location 168 before (red line), during (blue line), and after (red line) its residency. Before residency, amino acids have a lower average propensity (red dashed line) than they did at the time of a substitution (green circle), indicating that substitutions in the rest of the protein randomly preadapt the position to make the new amino acid relatively acceptable before substitution. Subsequently, the average propensity of the resident amino acid (blue dashed line) rises. After substitution away from the resident amino acid (cyan circle), the propensity falls again to a postresidency average (red dashed line) similar to the preresidency average.
David D. Pollock, Grant Thiltgen, and Richard A. Goldstein (2012)
Amino acid coevolution induces an evolutionary Stokes shift
Proceedings of the National Academy of Sciences, USA 109(21):E1352-9 Full-text
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