Intrinsically disordered proteins (IDPs) lack a well-defined 3D-structure but exhibit high flexibility and consist of ensembles of heterogeneous conformations covering a continuum of conformational space, from extended random coils to molten-globule like collapsed structures. IDPs play critical roles in cellular function, such as signal transduction, transcriptional regulation etc and are also directly/indirectly associated with several vital pathological conditions, such as Alzheimer’s and cancers. Therefore, in contrast to the conventional paradigm of protein function based on folded 3D-structure, emphasis has been shifted towards the understanding of disorder-flexibility-function relationships. Small-angle X-ray scattering (SAXS), nuclear magnetic resonance and Forster resonance energy transfer spectroscopy have been widely used to examine disorder-function relationships. However, the observables from these techniques are quite challenging to interpret. One of the major problems in interpreting these measurements is ensemble averaging over the heterogeneous conformations. In order to characterize the heterogeneous ensembles of IDPs, we performed molecular dynamics (MD) simulations. Further, the enhanced sampling method Hamiltonian replica-exchange molecular dynamics (HREMD) simulation was implemented to sample the equilibrium states possessed by IDPs. The simulation results are directly validated by experimental SAXS measurements without any reweighting and fitting parameters. In addition, the contribution from the explicit hydration shell is taken into account when calculating the theoretical SAXS profiles for comparison with experiment. The HREMD simulations of IDPs of varying lengths: RS-peptide (24 residues), Sic1 (90 residues), N-terminal of c-Src (95 residues), p15PAF (110 residues) and PaaA2 (142 residues), are in excellent agreement with their respective SAXS measurements. This demonstrates the synergistic approach of combining HREMD simulation and SAXS experiment to model the ensembles of IDP structures accurately.

Accurately modeling the heterogeneous ensemble of structures of intrinsically disordered proteins using enhanced sampling molecular dynamics simulations

2019 Spring National Meeting

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