Nejvíce citovaný článek - PubMed ID 35597655
The "good," the "bad," and the "hidden" in neutron scattering and molecular dynamics of ionic aqueous solutions
Salt bridges are ionic interactions that are of great importance in protein recognition. However, their structural description using X-ray crystallography or NMR may be inconclusive. Classical molecular dynamics (MD) used for the interpretation neglects electronic polarization, which results in artifactual overbinding. Here, we resolve the problem via charge scaling, which accounts for electronic polarization in a mean-field way. We study three salt bridges in insulin analogue. New NMR ensembles are generated via NOE-restrained MD using ff19SB and CHARMM36m force fields and the scaled-charge prosECCo75. Tens of μs of unrestrained MD show in a statistically converged manner that ff19SB induces a non-native salt bridge. This behavior is quantified via umbrella sampling of salt bridge dissociation, which indicates a rather high strength of up to 4 and 5 kcal mol-1 for CHARMM36m and ff19SB, respectively. In contrast, prosECCo75 gives a biologically reasonable dissociation barrier of 1 kcal mol-1. Our results indicate that a physically justified description of charge-charge interactions within a nonpolarizable MD framework reliably describes aqueous biomolecular systems.
- Publikační typ
- časopisecké články MeSH
Glycosaminoglycans (GAGs) are negatively charged polysaccharides found on cell surfaces, where they regulate transport pathways of foreign molecules toward the cell. The structural and functional diversity of GAGs is largely attributed to varied sulfation patterns along the polymer chains, which makes understanding their molecular recognition mechanisms crucial. Molecular dynamics (MD) simulations, thanks to their unmatched microscopic resolution, have the potential to be a reference tool for exploring the patterns responsible for biologically relevant interactions. However, the capability of molecular dynamics force fields used in biosimulations to accurately capture sulfation-specific interactions is not well established, partly due to the intrinsic properties of GAGs that pose challenges for most experimental techniques. In this work, we evaluate the performance of molecular dynamics force fields for sulfated GAGs by studying ion pairing of Ca2+ to sulfated moieties─N-methylsulfamate and methylsulfate─that resemble N- and O-sulfation found in GAGs, respectively. We tested available nonpolarizable (CHARMM36 and GLYCAM06) and explicitly polarizable (Drude and AMOEBA) force fields, and derived new implicitly polarizable models through charge scaling (prosECCo75 and GLYCAM-ECC75) that are consistent with our developed "charge-scaling" framework. The calcium-sulfamate/sulfate interaction free energy profiles obtained with the tested force fields were compared against reference ab initio molecular dynamics (AIMD) simulations, which serve as a robust alternative to experiments. AIMD simulations indicate that the preferential Ca2+ binding mode to sulfated GAG groups is solvent-shared pairing. Only our scaled-charge models agree satisfactorily with the AIMD data, while all other force fields exhibit poorer agreement, sometimes even qualitatively. Surprisingly, even explicitly polarizable force fields display a notable disagreement with the AIMD data, likely attributed to difficulties in their optimization and possible inherent limitations in depicting high-charge-density ion interactions accurately. Finally, the underperforming force fields lead to unrealistic aggregation of sulfated saccharides, which qualitatively disagrees with our understanding of the soft glycocalyx environment. Our results highlight the importance of accurately treating electronic polarization in MD simulations of sulfated GAGs and caution against over-reliance on currently available models without thorough validation and optimization.
- MeSH
- glykosaminoglykany * chemie MeSH
- kyseliny sulfonové chemie MeSH
- simulace molekulární dynamiky * MeSH
- sírany * chemie MeSH
- statická elektřina * MeSH
- vápník chemie MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- glykosaminoglykany * MeSH
- kyseliny sulfonové MeSH
- sírany * MeSH
- sulfamic acid MeSH Prohlížeč
- vápník MeSH
prosECCo75 is an optimized force field effectively incorporating electronic polarization via charge scaling. It aims to enhance the accuracy of nominally nonpolarizable molecular dynamics simulations for interactions in biologically relevant systems involving water, ions, proteins, lipids, and saccharides. Recognizing the inherent limitations of nonpolarizable force fields in precisely modeling electrostatic interactions essential for various biological processes, we mitigate these shortcomings by accounting for electronic polarizability in a physically rigorous mean-field way that does not add to computational costs. With this scaling of (both integer and partial) charges within the CHARMM36 framework, prosECCo75 addresses overbinding artifacts. This improves agreement with experimental ion binding data across a broad spectrum of systems─lipid membranes, proteins (including peptides and amino acids), and saccharides─without compromising their biomolecular structures. prosECCo75 thus emerges as a computationally efficient tool providing enhanced accuracy and broader applicability in simulating the complex interplay of interactions between ions and biomolecules, pivotal for improving our understanding of many biological processes.
In the last quarter-century, the field of molecular dynamics (MD) has undergone a remarkable transformation, propelled by substantial enhancements in software, hardware, and underlying methodologies. In this Perspective, we contemplate the future trajectory of MD simulations and their possible look at the year 2050. We spotlight the pivotal role of artificial intelligence (AI) in shaping the future of MD and the broader field of computational physical chemistry. We outline critical strategies and initiatives that are essential for the seamless integration of such technologies. Our discussion delves into topics like multiscale modeling, adept management of ever-increasing data deluge, the establishment of centralized simulation databases, and the autonomous refinement, cross-validation, and self-expansion of these repositories. The successful implementation of these advancements requires scientific transparency, a cautiously optimistic approach to interpreting AI-driven simulations and their analysis, and a mindset that prioritizes knowledge-motivated research alongside AI-enhanced big data exploration. While history reminds us that the trajectory of technological progress can be unpredictable, this Perspective offers guidance on preparedness and proactive measures, aiming to steer future advancements in the most beneficial and successful direction.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
It is established that the rates of solvent exchange at interfaces correlate with the rates of a number of mineral reactions, including growth, dissolution and ion sorption. To test if solvent exchange is limiting these rates, quasi-elastic neutron scattering (QENS) is used here to benchmark classical molecular dynamics (CMD) simulations of water bound to nanoparticulate calcite. Four distributions of solvent exchanges are found with residence times of 8.9 ps for water bound to calcium sites, 14 ps for that bound to carbonate sites and 16.7 and 85.1 ps for two bound waters in a shared calcium-carbonate conformation. By comparing rates and activation energies, it is found that solvent exchange limits reaction rates neither for growth nor dissolution, likely due to the necessity to form intermediate states during ion sorption. However, solvent exchange forms the ceiling for reaction rates and yields insight into more complex reaction pathways.
- Publikační typ
- časopisecké články MeSH
