Partial mimicry of the microtubule binding of tau by its membrane binding.

Tau, as typical of intrinsically disordered proteins (IDPs), binds to multiple targets including microtubules and acidic membranes. The latter two surfaces are both highly negatively charged, raising the prospect of mimicry in their binding by tau. The tau-microtubule complex was recently determined by cryo-electron microscopy. Here, we used molecular dynamics simulations to characterize the dynamic binding of tau K19 to an acidic membrane. This IDP can be divided into three repeats, each containing an amphipathic helix. The three amphipathic helices, along with flanking residues, tether the protein to the membrane interface. The separation between and membrane positioning of the amphipathic helices in the simulations are validated by published EPR data. The membrane contact probabilities of individual residues in tau show both similarities to and distinctions from native contacts with microtubules. In particular, a Lys that is conserved among the repeats forms similar interactions with membranes and with microtubules, as does a conserved Val. This partial mimicry facilitates both the membrane anchoring of microtubules by tau and the transfer of tau from membranes to microtubules.

Sequence-Dependent Backbone Dynamics of Intrinsically Disordered Proteins.

For intrinsically disordered proteins (IDPs), a pressing question is how sequence codes for function. Dynamics serves as a crucial link, reminiscent of the role of structure in sequence-function relations of structured proteins. To define general rules governing sequence-dependent backbone dynamics, we carried out long molecular dynamics simulations of eight IDPs. Blocks of residues exhibiting large amplitudes in slow dynamics are rigidified by local inter-residue interactions or secondary structures. A long region or an entire IDP can be slowed down by long-range contacts or secondary-structure packing. On the other hand, glycines promote fast dynamics and either demarcate rigid blocks or facilitate multiple modes of local and long-range inter-residue interactions. The sequence-dependent backbone dynamics endows IDPs with versatile response to binding partners, with some blocks recalcitrant while others readily adapting to intermolecular interactions.

Removing Thermostat Distortions of Protein Dynamics in Constant-Temperature Molecular Dynamics Simulations.

Molecular dynamics simulations are widely used to determine equilibrium and dynamic properties of proteins. Nearly all simulations, currently, are carried out at constant temperature, with a Langevin thermostat among the most widely used. Thermostats distort protein dynamics, but whether or how such distortions can be corrected has long been an open question. Here, we show that constant-temperature simulations with a Langevin thermostat dilate protein dynamics and present a correction scheme to remove the dynamic distortions. Specifically, ns-scale time constants for overall rotation are dilated significantly but sub-ns time constants for internal motions are dilated modestly, while all motional amplitudes are unaffected. The correction scheme involves contraction of the time constants, with the contraction factor a linear function of the time constant to be corrected. The corrected dynamics of eight proteins are validated by NMR data for rotational diffusion and for backbone amide and side-chain methyl relaxation. The present work demonstrates that even for complex systems like proteins with dynamics spanning multiple timescales, one can predict how thermostats distort protein dynamics and remove such distortions. The correction scheme will have wide applications, facilitating force-field parameterization and propelling simulations to be on par with NMR and other experimental techniques in determining dynamic properties of proteins.