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A Protein Sequence-Properties Evaluation Framework for Crystallization Screen Design

Dougall, David Stephen (2008) A Protein Sequence-Properties Evaluation Framework for Crystallization Screen Design. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The goal of the research was to develop a Protein-Specific Properties Evaluation (PSPE) framework that would aid in the statistical evaluation of variables for predicting ranges of and prior probability distributions for protein crystallization conditions. Development of such a framework is motivated by the rapid growth and evolution of the Protein Data Bank. Features of the framework that has been developed include (1) it is an instantiation of the "scientific method" for the framing and testing of hypotheses in an informatics setting, (2) the use of hidden variables, and (3) a negative result is still useful.The hidden variables examined in this study are related to the estimated net charge (Q) of the proteins under consideration. The Q is a function of the amino acid composition, the solution pH, and the assumed pKa values for the titratable amino acid residues. The protein's size clearly has a significant impact on the magnitude of the Q. Therefore, two additional variables were introduced to mitigate this effect, the specific charge (Qbar) and the average surface charge density (sigma).The principal observation is that proteins appear to crystallize at low values of Qbar and sigma. One problem with this observation is that "low" is a relative term and the frame of reference requires careful examination. The results are sufficiently weak that no prospective predictions appear possible although information of this type could be included with other weak predictors in a Bayesian predictor scheme. Additional work would be required to establish this; however that work is beyond the scope of the dissertation. Although many statistically significant correlations among Q-related quantities were noted, no evidence could be developed to suggest they were anything other than those expected from the additional information introduced with the hidden variables.Thus, the principal conclusions of this PSPE analysis are that (1) Qbar/sigma and other Q-related variables are of limited value as prospective predictors of ranges of values of crystallization conditions. Although this is a negative result, it is still useful in that it allows attention to be directed into more productive avenues.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Dougall, David Stephendsdst@pitt.eduDSDST
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairGopalakrishnan, Vanathivanathi@pitt.eduVANATHI
Committee MemberCooper, Gregory Fgfc@pitt.eduGFC
Committee MemberLyons-Weiler,
Committee MemberMay, Jerrold Hjerrymay@katz.pitt.eduJERRYMAY
Committee MemberRosenberg, Johh Mjmr@jmr2.xtal.pitt.eduROSENBRG
Date: 4 January 2008
Date Type: Completion
Defense Date: 27 October 2006
Approval Date: 4 January 2008
Submission Date: 1 October 2007
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Biomedical Informatics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: charge; PDB; pH; protein crystallization
Other ID:, etd-10012007-171912
Date Deposited: 10 Nov 2011 20:02
Last Modified: 15 Nov 2016 13:50


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