Medical Research

University of Kansas

Liskin Swint-Kruse, Antonio Artigues, Aron Fenton, Joseph Fontes, Bruno Hagenbuch, John Karanicolas, Alexey Ladokhin, Audrey Lamb, Paul Smith
Lawrence, KS
$1,000,000
December 2016

Protein engineering and personalized medicine would be significantly advanced if functional outcomes from amino acid mutations could be more accurately predicted.  Although many computer algorithms have been developed for that purpose, they have met with limited success.  Indeed, several common assumptions underlying these algorithms do not apply to a particular group of amino acid positions that are altered during evolution (nonconserved positions).  Among the characteristics of these positions, amino acid substitutions can dial function “up” or “down,” in a manner analogous to changing the dials on a stereo.  Since these “rheostat” positions appear to be wide-spread in many proteins, a team of investigators at the University of Kansas Medical Center, the University of Kansas – Lawrence, Kansas State University and Fox Chase Cancer Center seeks to develop a library of rheostat positions to guide and benchmark future computations.  By comparing and contrasting key nonconserved positions in proteins of distinct structural classes (globular soluble, integral membrane, and intrinsically disordered), the investigators will develop general methods to identify rheostat positions within a protein.  By generating biophysical data for representative proteins that have mutations at rheostat positions, the investigators will formulate new amino acid substitution rules for these locations.  Results from these studies will provide the critical information needed to improve mutation prediction algorithms.

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