Tau is an intrinsically disordered protein (IDP) implicated in Alzheimer’s disease. Under physiological conditions, tau associates with microtubules and regulates their dynamics, whereas during the progression of neurodegeneration tau dissociates from microtubules, misfolds and creates deposits in the brain tissue. To unravel the conformational properties of microtubule binding tau sequence located in its proline rich region 214Ser-231Thr the monoclonal antibody Tau5 with epitope in this region was used as a tau protein surrogate binding partner [1]. We have determined the conformation of 16 amino acid tau peptide bound in antibody combining site. The stability of this X-ray observed conformation was probed by molecular dynamics simulation. The simulation results were compared with the results obtained for a peptide with mutation T220A that has shown decreased affinity for Tau5 antibody in biophysical measurements.
To this end we have performed unrestrained MD simulations with 9 amino acid long tau peptide 218PPTREPKKV226 that contains all residues that are in contact with antibody paratope in the X-ray structure of the complex, for both wild type and mutated peptide.
Acknowledgement: This work was supported by the Slovak Research and Development Agency under the contract No. LPP-0038-09 and by VEGA grant 2/0177/15.