Biomedical Engineering Reference
In-Depth Information
Modeling Proteins at the Interface of Structure,
Evolution, and Population Genetics
Ashley I. Teufel, Johan A. Grahnen, and David A. Liberles
1
Introduction
Biological systems span multiple layers of organization and modeling across layers
of organization enables inference that is not possible by analyzing just one layer.
An example of this is seen in an organism's fitness, which can be directly impacted
by selection for output from a metabolic or signal transduction pathway. Even
this complex process is already several layers removed from the environment and
ecosystem. Within the pathway are individual enzymatic reactions and protein-
protein, protein-small molecule, and protein-DNA interactions. Enzymatic and
physical constants characterize these reactions and interactions, where selection
dictates ranges and thresholds of values that are dependent upon values for other
links in the pathway. The physical constants (for protein-protein binding, for
example) are dictated by the amino acid sequences at the interface. These constants
are also constrained by the amino acid sequences that are necessary to maintain
a properly folded structure as a scaffold to maintain the interaction interface. As
sequences evolve, population genetic and molecular evolutionary models describe
the availability of combinations of amino acid changes for selection, depending
in turn on parameters like the mutation rate and effective population size. As
the systems biology level of constraints has not been thoroughly characterized, it
is this multiscale modeling problem that describes the interplay between protein
biophysical chemistry and population genetics/molecular evolution that we will
describe.
There are three main trajectories in multiscale modeling at the interface of
protein structure and evolutionary biology. The first trajectory involves simulation
and forward evolution to describe both biophysical and evolutionary processes.
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