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                       BIOINFORMATICS COLLOQUIUM
                    School of Computational Sciences
                        George Mason University
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                     Engineering thermostability:
               Toward the design of highly stable protein
         mutants that maintain function at standard conditions

                           Dennis Livesay
            California State Polytechnic University, Pomona

                        Tuesday, March 23, 2004
                                4:30 pm
                 Verizon Auditorium, Prince William Campus

An especially important protein engineering problem relates to the
relatively poor stability of many protein therapeutics and industrial
enzyme catalysts. Our lab is therefore focused on the development of
strategies to confer increased stability to promising protein
targets. There has been some success along these lines in the
literature. However, increased stability often occurs at the expense of
function at standard conditions, generally due to over-rigidifying the
protein structure. This challenge is a key obstacle and is preventing
protein-based technologies from becoming more ubiquitous. In this talk,
I will discuss three computational developments from our lab to resolve
conundrum. The first is a robust bioinformatic methodology to identify
which portions of the protein are most likely related to proper
function. We show that our method, based on phylogenetic motifs, is able
to reliably predict key functionality across a diverse protein
dataset. These results provide critical knowledge which can be used to
increase the likelihood of maintaining function in subsequent design
endeavors. The second and third are biophysical models used to screen
protein mutants for increased stability. In the second, we use continuum
electrostatic theory to optimize protein surfaces, thus leading to
increased stability. In the third, we present a powerful Distance
Constraint Model, which is an accurate free energy calculation that
explicitly accounts for protein flexibility. The DCM is built upon a
mechanical description (called network rigidity) of the protein
structure. Network rigidity efficiently identifies all rigid and
flexible protein substructures and is used to correctly sum up component
entropies. An additional advantage of this method is that network
rigidity identifies all allosteric motions within the protein structure,
meaning it can be used to gauge the likelihood of effecting proper
protein function. For more information, visit:
http://www.csupomona.edu/~drlivesay/.

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Refreshments are served at 4:00 pm.  Find the schedule and directions at
http://www.binf.gmu.edu/colloq.html