Immunogenic sites of intrinsically disordered proteins


Intrinsically disordered protein (IDP) tau, involved in Alzheimers disease, is able to form stable complexes with specific monoclonal antibodies. Recently we obtained a panel of X-ray structures of pairs antibody/tau peptide, together with data about the kinetics and thermodynamic of antibody-tau peptide complex formation. In the SIVVP project we plan to corroborate determined structural and biophysical features of IDP interaction by molecular modeling approach to better understand the mode of IDP recognition by interaction partner and to disclose the role of IDP structural propensities to complex formation.

Výpočtové stredisko SAV, Odbor vysokovýkonnej výpočtovej techniky
Vedecká časť: 

Scientific aims:

1. To elucidate the relationship between solution conformation of disordered tau peptide and its conformation in the complex with antibody

2. To determine the structural base of observed affinity changes upon mutation of contact and adjacent residues in tau peptide epitope

3. To compare the suitability of existing force-fields on the study of IDP tau complexes by molecular modelling

References to published previous work:

1.            Cehlar, Ondrej; Skrabana, Rostislav; Kovac, Andrej; Kovacech, Branislav; Novak, Michal Crystallization and preliminary X-ray diffraction analysis of tau protein microtubule-binding motifs in complex with Tau5 and DC25 antibody Fab fragments ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY AND CRYSTALLIZATION COMMUNICATIONS 2012, 68, 1181-1185

2.            Skrabana, Rostislav; Cehlar, Ondrej; Flachbartova, Zuzana; Kovac, Andrej; Ševčík, Jozef; Novak, Michal Crystallization and preliminary X-ray diffraction analysis of two peptides from Alzheimer PHF in complex with the MN423 antibody Fab fragment ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY AND CRYSTALLIZATION COMMUNICATIONS  2012, 68, 1186-1190

3.            Skrabana R, Dvorsky R, Sevcik R, Novak M Monoclonal antibody MN423 as a stable mold facilitates structure determination of disordered tau protein. Journal of Structural Biology 2010, 171, 74-81

4.            Sevcik J, Skrabana R, Kontsekova E, Novak M Structure Solution of Misfolded Conformations Adopted by Intrinsically Disordered Alzheimer's Tau Protein. Protein and Peptide Letters 2009, 16 (1) 61-64

5.            Sevcik J, Skrabana R, Dvorsky R, Csokova N, Iqbal K, Novak M. X-ray structure of the PHF core C-terminus: Insight into the folding of the intrinsically disordered protein tau in Alzheimer's disease.FEBS Lett. 2007 Dec 22;581(30):5872-5878

Socioekonomický a technologický dopad: 

The project can boost progress mainly in two directions:

1. Better knowledge of binding mechanisms of IDP can promote better understanding of pathogenesis of degenerative diseases involving IDP aggregates as toxic moieties.

2. Critical evaluation of force field usage for the IDP molecular modelling can bring new insights into good practice of IDP structure study by MM.

Technická časť: 

In the project we plan to calculate µs trajectories of medium-sized peptides in explicit water. We plan to study a panel of peptides with various size and point mutations. For selected peptide combinations we plan to repeat calculations using alternative force fields. For performing molecular dynamics simulations we preferentially plan to adopt NAMD software ( It is envisaged that for certain types of force filed the software GROMACS ( will be used. Due to relatively long simulation times we plan to use roughly 10-20 days of machine time on ten nodes.

Prepojenie s grantovými úlohami: 
VEGA 2/0163/13 VEGA 2/0177/15 COST Action BM1405
1 000.00