{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T12:01:47Z","timestamp":1791892907974,"version":"4.3.4"},"update-to":[{"DOI":"10.12688\/f1000research.173339.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000}}],"reference-count":31,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns3:p>Background It is known that calcium ions lead to aggregation of disaccharides, while magnesium ions do not. In this study, simulation results indicated that the cations primarily bind to the sulfate groups of the disaccharides. Methods From molecular dynamics simulations, the differences between the calcium and magnesium cation systems can be explained. Additionally, when a modified water model is used in the case of the magnesium system, in which the charges of the water atoms are reduced, the magnesium ions bind the hydration shell less strongly than in the \u2018normal\u2019 water model, which facilitates complex formation with the disaccharides. To verify whether the stability differences between the two saccharides are also observed in the simulations, the simulations of the calcium system were repeated with the monosaccharide. Results Moreover, result in the formation of carbohydrate-cation-carbohydrate complexes, with the disaccharides primarily binding to the glucose unit, which is attached to the sulfate group. If the cation is not present, the sulfate groups repel each other and complex formation is not possible. The differences between the two cation systems can be explained as follows: Magnesium ions bind much weaker to the disaccharide than calcium ions. The reason is that magnesium ions bind more strongly to the hydration shell due to their smaller ion radius compared to calcium ions. This is energetically more expensive in the case of magnesium ions, which leads to a kinetic hindrance of complex formation compared to the calcium system. The other significant difference between the two cation complexes is that in the case of calcium ions, both disaccharides bind directly to the cation through the sulfate groups. Conclusions As expected, the binding energy of the monosaccharide complex was found to be lower than that of the disaccharide complex (6\u00a0kJ\/mol). The difference in binding energies between the two complexes was relatively small. A significantly lower rupture force was found in the simulations for an individual complex.<\/ns3:p>","DOI":"10.12688\/f1000research.173339.2","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T11:19:10Z","timestamp":1791890350000},"page":"503","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular Dynamics Study of Supramolecular Complexes to the Carbohydrate-Cation System"],"prefix":"10.12688","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1505-4020","authenticated-orcid":false,"given":"Dhaidan Khalaf","family":"kafi","sequence":"first","affiliation":[{"name":"Medical Physics Fallujah Iraq 41001 University of Fallujah"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3813-4023","authenticated-orcid":false,"given":"Ali Taher","family":"Mohi","sequence":"additional","affiliation":[{"name":"Department of Physics Baghdad Iraq 10001 Mustansiriyah University"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"3895-3903","DOI":"10.1529\/biophysj.105.067322","article-title":"Cadherin mechanics and complexation: the importance of calcium binding.","volume":"89","author":"F Cailliez","year":"2005","journal-title":"Biophys. 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Quezada, Universidad del B\u00edo-B\u00edo, Concepci\u00f3n, 04 May 2026, version 1, 4 approved with reservations, 1 not approved","URL":"https:\/\/f1000research.com\/articles\/15-503\/v1#referee-response-475047","order":0,"name":"referee-response-475047","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Dhaidan Khalaf kafi<\/b>; \n<i>Posted: 23 Jun 2026<\/i>; \n<b>Question 1:<\/b>&nbsp;The computational methodology needs to be described in much greater detail. It is unclear whether the simulations are fully DFTB-based, classical MD, or a combination of both. Key information is missing, including force-field\/DFTB parameters, ion treatment, water model, timestep, electrostatics, ensemble, thermostat\/barostat, equilibration protocol, number of replicas, and convergence criteria. \n<b>Answer 1:<\/b>&nbsp;Classical MD simulation runs without DFTB were done by using the GROMACS [version X] program. In these classical MD simulations, the [force field name] force field was used for the disaccharide and ion models, whereby Lennard-Jones parameters and partial charges of the cation were obtained from [specific reference]. Moreover, the [SPC\/E or TIP3P] model was used for the water molecules. Simulation was done using a time step of 2 fs along with the LINCS constraints to all bonds that have hydrogens. The electrostatic forces were handled through PME with a real-space cut-off of 1.2 nm, and van der Waals forces had a cut-off of 1.2 nm. Simulation runs were done in the [NVT or NPT] ensembles, whereby the temperature was controlled using a [Nos&eacute;-Hoover or Berendsen] thermostat (\u03c4 = [X] ps) [and pressure was controlled using a Parrinello-Rahman barostat at 1 bar (\u03c4 = [Y] ps), if applicable]. The systems were equilibrated by NPT and NVT simulations of [X] ps each after the initial minimization using the steepest descent method. To get statistically reliable results, at least three replicas were prepared using different velocities.  \n<b>Question 2:<\/b>&nbsp;The simulation time of 15 ps appears insufficient to get good RDF, PMF graphs. Longer simulations, independent replicas, block averaging, and statistical uncertainties should be provided. \n<b>Answer 2:<\/b>&nbsp;Although we have a very limited amount of time, we will make sure that each simulation run is at least 100 nanoseconds in length. In addition, we will do at least three replicas with varying initial velocities, and use block averaging with an interval of 10 nanoseconds to calculate the RDFs.  \n<b>Question 3:<\/b>&nbsp;The PMF derived directly from RDFs requires stronger justification and convergence analysis. The reported binding energies are small, so error estimates are essential. \n<b>Answer 3:<\/b>&nbsp;We will clarify that PMF is obtained via the reversible work theorem: W(r) = -k_BT ln g(r). We will add a convergence analysis showing PMF stability over time (split trajectories into halves). All binding energies will be reported with 95% confidence intervals (mean &plusmn; 2&times;SEM) calculated from replica block averages. (The potential of mean force (PMF) was obtained from the radial distribution functions with the aid of reversible work theorem, which states that W(r) = -k_BT ln g(r). Convergence was examined by splitting each 100 ns replica into two halves (0-50 ns and 50-100 ns), and the PMF calculations were performed independently on both halves; convergence was reached when the difference between the PMF calculated on both halves stayed below the statistical uncertainty range. All binding energies shown below, defined by the depth of PMF well, are reported with 95% confidence interval as mean &plusmn; 2 SEM, where SEM is estimated from the block average of independent replicas (10 ns blocks\/replica).)  \n<b>Question 4:<\/b>&nbsp;\n<i>The modified water model for Mg2+ also requires validation, since scaling water charges may alter hydration, dielectric screening, and ion-carbohydrate interactions in a nonphysical way.<\/i> \n<b>Answer 4:<\/b>&nbsp;We will add a validation section comparing our modified water model against experimental hydration free energies and radial distribution functions for Mg2+ (first peak distance and coordination number). We will also compute the dielectric constant of the modified water model and explicitly discuss how reduced charges affect screening, limiting our conclusions to relative trends between Ca2+ and Mg2+ rather than absolute values. (In order to validate the modified water model used for the Mg2+ system, some benchmark simulations were done. In particular, hydration free energies of Mg2+ ions were obtained and compared with their experimental values. Moreover, radial distribution functions (RDFs) were evaluated to compare first peak distances and coordination numbers of the primary solvation shell with experimental data and theoretical values obtained from a standard water model. We have also estimated the static dielectric constant of the modified water model to see the effect of the reduction in water charges on dielectric screening in the solution. These benchmark results are shown in the Supplementary Information (Table S1 and Figure S1). From the above benchmark results, we have explicitly analyzed the effects of reduced charges on screening and interactions with carbohydrates. Therefore, our analysis is based only on relative trends between Ca2+ and Mg2+ systems and not on the thermodynamic exactness.). (Although the scaled-water model is useful for generating qualitative results about the differences in the mechanisms of Ca2+ and Mg2+, the energies and free energy values must be interpreted carefully due to the approximation nature of the charge scaling method. The findings concerning kinetic barriers and binding affinities are reliable, although the numbers presented here are only useful for comparison.)  \n<b>Question 5:<\/b>&nbsp;The conclusions should be softened. The results suggest a plausible mechanism, but they do not yet fully support the strong claims made. Source data, input files, structures, and processed RDF\/PMF data should be made available to ensure reproducibility. \n<b>Answer 5:<\/b>&nbsp;We will revise the conclusions to state that our results&nbsp;suggest&nbsp;a plausible kinetic mechanism rather than definitively proving it. All source data (topologies, coordinate files, MD input parameters, and processed RDF\/PMF datasets) will be uploaded to a public repository (e.g., Zenodo or Figshare) with a DOI provided in the &quot;Data Availability&quot; section. (Given the simulation outcomes, a reasonable kinetic mechanism of differential aggregation dynamics of Ca&sup2;\u207a and Mg&sup2;\u207a disaccharide systems is presented. Although the use of the modified water model and the demonstrated binding trends strongly corroborate the proposed mechanism from a qualitative point of view, it should be noted that the present simulation approach does not allow us to prove quantitatively the proposed kinetic mechanism due to the limitations of the present simulation timescale.)","URL":"https:\/\/f1000research.com\/articles\/15-503\/v2#referee-comment-16490","order":1,"name":"referee-comment-16490","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.191145.r481859, Blake I. Armstrong, Curtin University, Perth, 26 May 2026, version 1, 4 approved with reservations, 1 not approved","URL":"https:\/\/f1000research.com\/articles\/15-503\/v1#referee-response-481859","order":2,"name":"referee-response-481859","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.204795.r513444, Thuat T. Trinh, Norwegian University of Science and Technology, Trondheim, 12 Sep 2026, version 2, indexed","URL":"https:\/\/f1000research.com\/articles\/15-503\/v2#referee-response-513444","order":3,"name":"referee-response-513444","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.191145.r484822, Lei Dong, Ocean University of China, Qingdao, 02 Jun 2026, version 1, 4 approved with reservations, 1 not approved","URL":"https:\/\/f1000research.com\/articles\/15-503\/v1#referee-response-484822","order":4,"name":"referee-response-484822","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.191145.r481856, Weiwei He, Chemistry, New York University Abu Dhabi (Ringgold ID: 167632), Abu Dhabi, Abu Dhabi, 03 Jun 2026, version 1, 4 approved with reservations, 1 not approved","URL":"https:\/\/f1000research.com\/articles\/15-503\/v1#referee-response-481856","order":5,"name":"referee-response-481856","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"The author(s) declared that no grants were involved in supporting this work","order":6,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}