Simulations of Amyloid-Forming Peptides in the Crystal State

Abstract

There still is little treatment available for amyloid diseases, despite their significant impact on individuals and the social and economic implications for society. One reason for this is that the physical nature of amyloid formation is not understood sufficiently well. Therefore, fundamental research at the molecular level remains necessary to support the development of therapeutics. A few structures of short peptides from amyloid-forming proteins have been determined. These can in principle be used as scaffolds for designing aggregation inhibitors. Attempts to this end have often used the tools of computational chemistry, in particular molecular simulation. However, few simulation studies of these peptides in the crystal state have been presented so far. Hence, to validate the capability of common force fields (AMBER19SB, CHARMM36m, and OPLS-AA/M) to yield insight into the dynamics and structural stability of amyloid peptide aggregates, we have performed molecular dynamics simulations of twelve different peptide crystals at two different temperatures. From the simulations, we evaluate the hydrogen bonding patterns, the isotropic B-factors, the change in energy, the Ramachandran plots, and the unit cell parameters and compare the results with the crystal structures. Most crystals are stable in the simulations but for all force fields there is at least one that deviates from the experimental crystal, suggesting more work is needed on these models.

Martini on the Rocks: Can a Coarse-Grained Force Field Model Crystals?

“…Compared to our previous work using three atomistic force fields, AMBER19SB, CHARMM36m, and OPLS-AA/M, a much larger deviation of lattice parameters is observed for virtually all peptides using both the Parrinello–Rahman (which is the recommended barostat in Martini 3) and the Berendsen barostat (which is more resistant to fluctuations). The MVGGVV (1) crystal is destabilized and deformed in all M3, M3′, and M3″ models in a manner similar to that of AMBER19SB, CHARMM36m, and OPLS-AA/M force fields at room temperature, but to a larger degree.…”

“…However, the shift in the calculated RDF and the decrease in RDF height in the simulations, compared to the initial RDF at both cryo and room temperatures, confirm the melting of the peptide and transformation to a liquid state using both Parrinello–Rahman and Berendsen barostats for all three Martini 3 variants (Figures S19–S22). In contrast, an example RDF from our previous AA study using CHARMM36m shows that the hydrogen bond structure is maintained in AA simulations (Figure S23).…”

“…Clearly, the development of force fields necessitates an independent assessment of such models. The study of crystal lattices has been a key component in the history of molecular dynamics, and such studies have proven to be useful in investigating the quality of underlying force fields, establishing correlations between simulated ensembles and experimental structure factors. , Hence, in this work, we investigate whether the Martini 3 model can reproduce properties of crystals consisting of amyloid peptides and organic compounds that we have studied previously using AA models. , We present CG simulations of 12 amyloid peptide crystals at cryo temperature and the temperature used for growing the crystals and evaluate the stability of the crystal. To do so, we have performed crystal peptide simulations considering the “bare” Martini 3 (M3) force field, a variant including side chain restraints (M3′) and a variant including both side chain restraints and restraints on the intramolecular secondary structure (M3″) .…”

“…Examples of such benchmarks are available for the gas phase, ,, the liquid phase, − and the solid phase. , These studies have established the root-mean-square errors for predictions from atomistic force fields to be ∼7 kJ/mol for enthalpies of vaporization, , ∼3% for liquid densities, , 8 kJ/mol for enthalpies of sublimation, 5% for solid densities, and 40 K for the melting point . We recently extended this benchmarking work to a study of peptide crystals . In that study, we performed simulations of 12 peptide crystals using three modern atomistic force fields and found that some of the crystals deformed during long simulations (Table ).…”

“… 47 , 48 Hence, in this work, we investigate whether the Martini 3 model can reproduce properties of crystals consisting of amyloid peptides and organic compounds that we have studied previously using AA models. 49 , 50 We present CG simulations of 12 amyloid peptide crystals at cryo temperature and the temperature used for growing the crystals and evaluate the stability of the crystal. To do so, we have performed crystal peptide simulations considering the “bare” Martini 3 (M3) force field, a variant including side chain restraints (M3′) 51 and a variant including both side chain restraints and restraints on the intramolecular secondary structure (M3″).…”