4/5/2023 0 Comments Dispersio n![]() ![]() (33) Bonds involving hydrogen atoms were restrained to their equilibrium lengths using the M-SHAKE algorithm. The systems were initially equilibrated at 300 K and 1 bar for 1 ns using the Desmond software (28) production runs at 300 K were performed in the NPT ensemble (29-31) with the Anton specialized hardware (32) using a 2.5 fs time step and a 1:2 RESPA scheme. The CHARMM22 force field (27) was used to represent the ions. Initial extended structures of IN, protein L, and CspTm were solvated in cubic 70 × 70 × 70 Å 3 boxes, containing ∼10 000 water molecules and 0.1 M NaCl, whereas the larger α-synuclein and prothymosin-α were solvated in an ∼100 × 100 × 100 Å 3 box containing ∼40 000 water molecules and 0.1 M NaCl. Simulations were started from an extended conformation. These proteins were chosen, as there is a large amount of experimental data characterizing their unfolded states under physiological conditions. We performed simulations of five proteins: the apo N-terminal zinc-binding domain of HIV-1 integrase (IN) (PDB entry 1WJB), (23) the immunoglobulin-binding domain of protein L (PDB entry 2PTL), (24) the cold-shock protein from Thermotoga maritima (CspTm) (PDB entry 1G6P), (25) α-synuclein (PDB entry 1XQ8), (26) and prothymosin-α. Remarkably, this discrepancy is largest for those intermolecular geometries corresponding to the most stable, hydrogen-bonded conformations. In agreement with earlier results, (22) our calculations indeed indicate that all tested water models fail to capture the full extent of dispersion stabilization energy. (2, 20, 21) We evaluate this hypothesis by performing high-level quantum mechanics (QM) calculations. We conjecture that an important reason for the discrepancies between these simulated and experimental results is that current water models severely underestimate water–water and water–solute dispersion interactions. We find that all combinations of force fields and water models tested result in disordered states that are overly compact, with radii of gyration ( R g) that are in strong disagreement with experimental observations. In this paper, we begin by systematically assessing the ability of a number of commonly used protein force fields and water models to reproduce various structural properties of disordered proteins under physiological conditions. ![]() These results represent a significant step toward extending the range of applicability of MD simulations to include the study of (partially or fully) disordered protein states. ![]() We show that simulations of solvated proteins using this new water model typically result in disordered states that are substantially more expanded and in better agreement with experiment. To test this hypothesis, we create a new water model, TIP4P-D, that approximately corrects for these deficiencies in modeling water dispersion interactions while maintaining compatibility with existing physics-based models. We find that the water models typically used in MD simulations significantly underestimate London dispersion interactions, and speculate that this may be a possible reason for these erroneous results. Unfortunately, MD simulations using current physics-based models tend to produce disordered-state ensembles that are structurally too compact relative to experiments. Molecular dynamics (MD) simulations should in principle provide an ideal tool for elucidating the composition and behavior of disordered states at an atomic level of detail. Structural characterization of these disordered states using experimental methods can be challenging, since they are composed of a structurally heterogeneous ensemble of conformations rather than a single dominant conformation. Many proteins can be partially or completely disordered under physiological conditions. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |