The current study clearly demonstrates the promise of atomistic simulations for detailed characterization of IDP conformations, and at the same time reveals important limitations in the current implicit solvent protein force field that must be sufficiently addressed for reliable description of long-range structural features of the disordered ensembles.

Here, we utilize a recently developed replica exchange With guided annealing enhanced sampling technique to calculate well-converged atomistic conformational ensembles of the intrinsically disordered transactivation domain (TAD) of tumor suppressor p53 and several cancer-associat-ed mutants in an implicit solvent protein force field .

This suggests that the atomistic ensemble is overly compact, likely due to the known tendency of the GBSW/ SA implicit force field to over-stabilize intra-peptide interactions [55,56].

The success of the current simulations demonstrates the feasibility and promise of combining advanced sampling techniques and modern atomistic force fields , particularly With implicit solvent, for effective IDP simulations.

At the same time, important limitations remain in implicit solvent protein force fields , and the simulated ensembles are overly compact.

The current study thus also underpins the importance of continual development and optimization of implicit solvent protein force fields .

A possible strategy to overcome this fundamental limitation is to leverage significant recent advances in physics-based protein force fields and enhanced sampling techniques to calculate de novo structural ensembles [10,17].

An important caveat is, however, de novo ensembles will inevitably contain artifacts due to persisting limitations in the current protein force fields as well as conformational sampling capability.

The GBSW/ SA force field is based on the CHARMM22/CMAP protein force field [81—84], and has been previously optimized for simulation of conformational equilibria of small peptides.

For all residues, except the sulfenic acid, the AMBER99SB force field was used [44,45].

Sulfenic acid force field parameters were built using AMBER recommended procedure.

All bonded and VdW parameters were taken from the General AMBER Force Field [47].

From this information the traction force field can be reconstructed (Fig 1C) and correlated with the internal actin structure, including actin retrograde flow and SFs [19,20].

If it is chosen too large, the details of the force field are smoothed out and the overall force magnitude is too small.

The deviation between the theoretical prediction and experimental measurement is represented by the relative LZ-norm that ranges between 0 for perfect agreement and 1 for a vanishing force field .

Multiscale molecular dynamics simulations of the UraA symporter in phospholipid bilayers consisting of: 1) 1-palmitoyl 2—oIeoyl-phosphatidylcholine (POPC); 2) 1-palmitoyl 2—oleoyI-phosphatidylethanolamine (POPE); and 3) a mixture of 75% POPE, 20% 1-palmi-toyl 2—oleoyl-phosphatidylglycerol (POPG); and 5% 1-palmitoyl 2—oleoyI-diphosphatidylgly-cerol/cardiolipin (CL) to mimic the lipid composition of the bacterial inner membrane, were performed using the MARTINI coarse-grained force field to self-assemble lipids around the crystal structure of this membrane transport protein, followed by atomistic simulations.

Atomistic molecular dynamics (AT-MD) simulations were performed using the GROMOS96 53a6 force field that has been widely used in simulation studies of membrane proteins.

Coarse-grained molecular dynamics (CG-MD) simulations were performed using the MARTINI force field [22].

), corresponding to a lipid diffusion coefficient Dmdz/ (tX) = 10—6 cmZ/s, (or Dm2.5><10_7 cmZ/s, when accounting for the effective time scaling for the CG force field we used).

Notably, similar values of lipid diffusion constants have recently been reported in the literature [26,27] for comparable CG force fields , and a similar behavior was implied.

The receptors were converted to a CG representation under the MARTINI force field (version 2.1) [16—18] and a modified elastic network was applied, as reported previously in the literature [42].