Transient tertiary structures in tau, an intrinsically disordered protein

Abstract

An intrinsically disordered protein (IDP) does not have a definite 3D structure, and because of its highly flexible nature it evolves dynamically in very large and diverse regions of the phase space. A standard molecular dynamics run can sample only a limited region of the latter; even though this kind of simulation may be effective in sampling local temporary secondary structures, it is not sufficient to highlight properties that require a larger sampling of the phase space to be detected, like transient tertiary structures. But if the structure of an IDP is dynamically evolved using metadynamics (an algorithm that keeps track of the regions of the phase space already sampled), the system can be forced to wander in a much larger region of the phase space. We have applied this procedure to the simulation of tau, one of the largest totally disordered proteins. Combining the results of the simulation with small-angle X-ray scattering yields a significant improvement in the sampling of the phase space in comparison with standard molecular dynamics, and provides evidence of extended hairpin- and paperclip-like transient tertiary structures of the molecule. The more persistent tertiary pattern is a hairpin folding encompassing part of the N-terminal, the proline-rich domain, the former repeat and a functionally relevant part of the second repeat.

Keywords::

• transient tertiary structures
• tau protein
• intrinsically disordered proteins
• metadynamics

Acknowledgements

The authors are indebted to Dr Petra Pernot for providing access to the beamline at ESRF and for assistance during the experiment. The computer simulation was supported by CASPUR (Italy) under a Standard HPC Grant 2012 (std12-039).

Notes

^1. The data bank DisProt (http://www.disprot.org) lists nearly 700 disordered proteins; the entry for tau is DP00126.

^2. A description of the different isoforms can be found at http://www.uniprot.org/uniprot/P10636

^3. GROMACS release 4.5.3, http://www.gromacs.org; box volume, 15,253 nm³; ffamber99 force field; SPC/E water model; time step, 2 fs; modified Berendsen thermostat, Parrinello–Rahman pressure coupling.

^4.; deposition stride,  ps; height  kJ/mol; Gaussian width,  nm; limits on : upper UW ALL = 7.0 nm, lower LW ALL = 5.5 nm.

^5. GAJOE parameters were set as follows: number of generations, 1000; number of ensembles, 50; number of curves per ensemble, 20; number of mutations per ensemble, 10; number of crossings per generation, 20.