STUDIES OF THE ELECTROSTATIC PROPERTIES OF PEROXIREDOXINS

Peroxiredoxins (Prxs) are peroxidases which can also regulate cell signaling pathways, apoptosis, and differentiation. During catalysis, Prxs exhibit cysteine-dependent reactivity which requires the deprotonation of a peroxidatic cysteine (Cp) via a lowered pKa in the initial step. Local conformational changes from a fully folded (FF) configuration to a locally unfolded (LU) configuration facilitate the formation of a disulfide bond between Cp and another resolving cysteine (Cr), which completes the reaction cycle. The particular enzyme mechanism classifies the whole Prxs family of proteins into 1-Cys, typical 2-Cys, and atypical 2-Cys Prx subfamilies. Typical 2-Cys Prxs are obligate homodimers, and usually form decamers in solution. Because the molecular function of Prxs depends largely on the protonated state of Cp, the electrostatics near this residue is particularly important. In this dissertation, molecular dynamics (MD) simulations were combined with macroscopic electrostatics with atomic detail (MEAD) model to study the electrostatics of two typical 2-Cys Prxs in different local conformations and different oligomeric states. The results provide insight on the structure-function relationship of typical 2-Cys Prxs: (1) how local conformational change affects Cp pKa and nearby electrostatics and (2) the reasons why typical 2-Cys Prxs usually oligomerize into a decamer in solution. Important structural features that are used by Prxs to lower the Cp pKa and hence to facilitate the catalysis were identified. Some of the predictions that are made according to the calculations are quantitatively consistent with experimental results. In addition, a new method has been developed to quantify the similarity between two electrostatic potentials. The electrostatic potentials near active sites of all Prxs proteins with known crystal structures have been calculated and clustered into different subfamilies according to this new method. Each subfamily corresponds to a subfamily of Prxs that are classified according to the sequence similarity. This method was used to identify the common electrostatic features shared by all members of a subfamily, and can be used to predict the subfamily of newly solved protein structures.

Grantor dc:publisher

Wake Forest University

Year dc:date.issued

2010

Author dc:creator

• Yuan, Ye

• molecular dynamics

Language dc:language.iso

en_US

Handle dc:identifier.uri

http://hdl.handle.net/10339/14718

OAI identifier oai:identifier

oai:wakespace.lib.wfu.edu:10339/14718