Computational chemistry is an important tool in numerous scientific disciplines, including drug discovery and structural biology. Coarse-grained models offer simple representations of molecular ...systems that enable simulations of large-scale systems. Because there has been an increase in the adoption of such models for simulations of biomolecular systems, critical evaluation is warranted. Here, the stability of the amyloid peptide and organic crystals is evaluated using the Martini 3 coarse-grained force field. The crystals change shape drastically during the simulations. Radial distribution functions show that the distance between backbone beads in β-sheets increases by ∼1 Å, breaking the crystals. The melting points of organic compounds are much too low in the Martini force field. This suggests that Martini 3 lacks the specific interactions needed to accurately simulate peptides or organic crystals without imposing artificial restraints. The problems may be exacerbated by the use of the 12-6 potential, suggesting that a softer potential could improve this model for crystal simulations.
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.
Free-energy calculations are crucial for investigating biomolecular interactions. However, in theoretical studies, the neglect of electronic polarization can reduce predictive capabilities, ...specifically for free-energy calculations. To effectively mimick polarization, we explore a
(CS) model, aiming to narrow the gap between computational and experimental results. The model requires quantum-level partial charge calculations of the molecule in different environments, combined with atomistic MD simulations. Studying three different anti-cancer drug molecules with three different phospholipid membranes, we show that the method significantly improves agreement with available experimental data. In contrast, using conventional fixed charge atomistic methods, qualitative discrepancies with experiments are observed, and we show that neglecting polarization may lead to an unphysical free energy sign inversion. While the CS method is here applied to anti-cancer drug-membrane translocation, it could be used more generally to study processes considering solvent effects.
Computational methods to understand interactions in bio-complex systems are however limited to time-scales typically much shorter than in Nature. For example, on the nanoscale level, interactions ...between nanoparticles (NPs)/molecules/peptides and membranes are central in complex biomolecular processes such as membrane-coated NPs or cellular uptake. This can be remedied by the application of
Jarzynski's equality where thermodynamic properties are extracted from non-equilibrium simulations. Although, the out of equilibrium work leads to non-conservative forces. We here propose a correction Pair Forces method, that removes these forces. Our proposed method is based on the calculation of pulling forces in backward and forward directions for the Jarzynski free-energy estimator using steered molecular dynamics simulation. Our results show that this leads to much improvement for NP-membrane translocation free energies. Although here we have demonstrated the application of the method in molecular dynamics simulation, it could be applied for experimental approaches.
