posted on 2020-10-01, 03:43authored byJoshua
W. Wilkerson, Addison K. Smith, Kristen M. Wilding, Bradley C. Bundy, Thomas A. Knotts
Functionalization
is often needed to harness the power of proteins
for beneficial use but can cause losses to stability and/or activity.
State of the art methods to limit these deleterious effects accomplish
this by substituting an amino acid in the wild-type molecule into
an unnatural amino acid, such as p-azidophenylalanine
(pAz), but selecting the residue for substitution a priori remains
an elusive goal of protein engineering. The results of this work indicate
that all-atom molecular dynamics simulation can be used to determine
whether substituting pAz for a natural amino acid will be detrimental
to experimentally determined protein stability. These results offer
significant hope that local deviations from wild-type structure caused
by pAz incorporation observed in simulations can be a predictive metric
used to reduce the number of costly experiments that must be done
to find active proteins upon substitution with pAz and subsequent
functionalization.