Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data and Computer Simulations

Poster Abstracts

53-POS Board 13 Generation and Assessment of Dynamic Structural Ensembles of Parvulin-type Peptidyl- Prolyl Isomerases by Externally Restrained Molecular Dynamics Simulation Bertalan Kovács 1 , András Czajlik 1 , Perttu Permi 2 , Zoltán Gáspári 1 . 1 Pázmány Péter Catholic University, Budapest, Hungary, 2 University of Jyväskylä, Jyväskylä, Finland. Parvulins are a subtype of peptidyl-prolyl isomerases (PPIase) that catalyze the isomerization of the peptide bond preceding proline residues. They play a critical role in several biological processes like chromatin remodeling, transcription and nuclear receptor signaling, as well as in protein folding. While their three dimensional structure and the location of the active site is well- defined, the exact mechanism of their catalytic activity remains elusive. It is generally accepted that there is no breaking and reforming of the peptide bond, instead, isomerisation occurs through a twisted intermediate state. A recent analysis of dynamic structural ensembles of cyclophilin A proposed an electrostatic handle mechanism facilitated by the polarity of the carbonyl group of the peptide bond. In the presented study, externally restrained dynamical structural ensembles were generated using experimentally determined NOEs and S2 parameters for three distinct parvulins: SaPrsA, TbPin1 and CsPinA. The resulting ensembles show good agreement with the experimental parameters, including chemical shifts, but also show significant differences in the dynamics of the three enzymes. Analysis of the predominant motional modes in both the restrained and unrestrained ensembles as well as the role of the WW-domain in Pin1-type parvulins compared to the non-Pin1-type suggest a catalitically determining motion in the enzyme activity. It is concluded that modulation of the extent and dynamics of the identified motion accounts for the differences in the function of the distinct parvulins. The presented results were recently published in Czajlik et al. 2017, Sci Rep.

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