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Effect of zwitterionic monomer polymerization on water dynamics: a molecular dynamics simulation study supported by differential scanning calorimetry and terahertz spectroscopy

Polymer Journal volume 57, pages 1127–1139 (2025)Cite this article

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Abstract

The behavior of water molecules significantly influences the effectiveness of protein stabilizers and biomaterials. Although the polymerization of low-molecular-weight molecules enhances their functionality, the hydration states and water dynamics around polymers and small molecules are typically examined separately. Therefore, the effect of polymerization on water dynamics at the molecular level remains unclear. By density functional tight-binding molecular dynamics (DFTB-MD) simulations of five zwitterionic solute solutions, (trimethylamine N-oxide) (TMAO), the N-[3-(dimethylamino)propyl]acrylamide N-oxide (DMAO) monomer, poly(N-[3-(dimethylamino)propyl]acrylamide N-oxide) (PDMAO), the 2-methacryloyloxyethyl phosphorylcholine (MPC) monomer, and poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), the effects of polymerization on water dynamics were investigated. DMAO and MPC polymerization (to PDMAO and PMPC, respectively) promote the slow and rapid rotation of water molecules, respectively. In PDMAO, water molecules are trapped between side chains due to the formation of hydrogen bonds between water and PDMAO, resulting in slow water dynamics, whereas in PMPC, a reduction in the solvent-accessible surface area due to polymerization disrupts the hydrogen-bond network among the water molecules, resulting in acceleration of the rotational dynamics of water molecules. The hydration amount determined using differential scanning calorimetry (DSC) and terahertz time-domain spectroscopy (THz-TDS) is consistent with the MD simulation results, which provide molecular-level insights that advance the current understanding of water dynamics in small-molecule polymerization for potential functional enhancement.

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References

  1. Li Q, Wen C, Yang J, Zhou X, Zhu Y, Zheng J, et al. Zwitterionic Biomaterials. Chem Rev. 2022;122:17073–154.

    Article  CAS  PubMed  Google Scholar 

  2. Dargaville BL, Hutmacher DW. Water as the often neglected medium at the interface between materials and biology. Nat Commun. 2022;13:4222.

  3. Tanaka M, Mochizuki A. Clarification of the blood compatibility mechanism by controlling the water structure at the blood-poly(meth)acrylate interface. J Biomater Sci Polym Ed. 2010;21:1849–63.

    Article  CAS  PubMed  Google Scholar 

  4. Tanaka M, Mochizuki A. Effect of water structure on blood compatibility— thermal analysis of water in poly(meth)acrylate. J Biomed Mater Res A. 2004;68A:684–95.

    Article  CAS  Google Scholar 

  5. Hishida M, Anjum R, Anada T, Murakami D, Tanaka M. Effect of Osmolytes on Water Mobility Correlates with Their Stabilizing Effect on Proteins. J Phys Chem B. 2022;126:2466–75.

    Article  CAS  PubMed  Google Scholar 

  6. Anjum R, Nishimura SN, Kobayashi S, Nishida K, Anada T, Tanaka M. Protein Stabilization Effect of Zwitterionic Osmolyte-bearing Polymer. Chem Lett. 2021;50:1699–702.

    Article  CAS  Google Scholar 

  7. Fedotova MV. Compatible osmolytes - bioprotectants: Is there a common link between their hydration and their protective action under abiotic stresses?. J Mol Liq. 2019;292:111339.

    Article  CAS  Google Scholar 

  8. Hishida M, Kanno R, Terashima T. Hydration State on Poly(ethylene glycol)-Bearing Homopolymers and Random Copolymer Micelles: In Relation to the Thermoresponsive Property and Micellar Structure. Macromolecules. 2023;56:7587–96.

    Article  CAS  Google Scholar 

  9. Israelachvili J, Wennerström H. Role of hydration and water structure in biological and colloidal interactions. Nature. 1996;379:219–25.

    Article  CAS  PubMed  Google Scholar 

  10. Hishida M. Correlation between Hydration States and Self-assembly Structures of Phospholipid and Surfactant Studied by Terahertz Spectroscopy. J Oleo Sci. 2024;73:419–27.

    Article  CAS  PubMed  Google Scholar 

  11. Bagchi B. Water Dynamics in the Hydration Layer around Proteins and Micelles. Chem Rev. 2005;105:3197–219.

    Article  CAS  PubMed  Google Scholar 

  12. Laage D, Elsaesser T, Hynes JT. Water Dynamics in the Hydration Shells of Biomolecules. Chem Rev. 2017;117:10694–725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Leitenstorfer A, Moskalenko AS, Kampfrath T, Kono J, Castro-Camus E, Peng K, et al. The 2023 terahertz science and technology roadmap. J Phys D Appl Phys. 2023;56:223001.

    Article  CAS  Google Scholar 

  14. Shiraga K, Adachi A, Nakamura M, Tajima T, Ajito K, Ogawa Y. Characterization of the hydrogen-bond network of water around sucrose and trehalose: Microwave and terahertz spectroscopic study. J Chem Phys. 2017;146:105102.

    Article  PubMed  Google Scholar 

  15. Rahman MK, Yamada T, Yamada NL, Higuchi Y, Seto H. Hydration Water Dynamics in Zwitterionic Phospholipid Membranes Mixed with Charged Phospholipids. J Phys Chem B. 2025;129:18.

    Article  Google Scholar 

  16. Schirò G, Fichou Y, Gallat FX, Wood K, Gabel F, Moulin M, et al. Translational diffusion of hydration water correlates with functional motions in folded and intrinsically disordered proteins. Nat Commun. 2015;6:1–8.

    Article  Google Scholar 

  17. Talon C, Smith LJ, Brady JW, Lewis BA, Copley JRD, Price DL, et al. Dynamics of Water Molecules in Glucose Solutions. J Phys Chem B. 2004;108:5120–6.

    Article  CAS  Google Scholar 

  18. Li B, Jain P, Ma J, Smith JK, Yuan Z, Hung HC, et al. Trimethylamine N-oxide–derived zwitterionic polymers: A new class of ultralow fouling bioinspired materials. Sci Adv. 2019;5:9562–76.

    Article  Google Scholar 

  19. Senaratne W, Andruzzi L, Ober CK. Self-assembled monolayers and polymer brushes in biotechnology: Current applications and future perspectives. Biomacromolecules. 2005;6:2427–48.

    Article  CAS  PubMed  Google Scholar 

  20. Raynor JE, Capadona JR, Collard DM, Petrie TA, García AJ. Polymer brushes and self-assembled monolayers: Versatile platforms to control cell adhesion to biomaterials (Review). Biointerphases. 2009;4:FA3–16.

    Article  CAS  PubMed  Google Scholar 

  21. Zhang Z, Zhang M, Chen S, Horbett TA, Ratner BD, Jiang S. Blood compatibility of surfaces with superlow protein adsorption. Biomaterials. 2008;29:4285–91.

    Article  CAS  PubMed  Google Scholar 

  22. Kawabe S, Seki M, Tabata H. Evaluation of hydration in a water-soluble polymer by terahertz spectroscopy. Appl Phys Lett. 2016;108:81103.

    Article  Google Scholar 

  23. Tominaga T, Hishida M, Murakami D, Fujii Y, Tanaka M, Seto H. Experimental evidence of slow mode water in the vicinity of poly (ethylene oxide) at physiological temperature. J Phys Chem B. 2022;2022:1758–67.

    Article  Google Scholar 

  24. Nakada M, Ishida H, Furushima Y. Structural and dynamical characterisation of intermediate water interacting polyvinyl pyrrolidone. Materialia (Oxf). 2020;12:100743.

    Article  CAS  Google Scholar 

  25. Keefe AJ, Jiang S. Poly(zwitterionic)protein conjugates offer increased stability without sacrificing binding affinity or bioactivity. Nat Chem. 2011;4:59–63.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Baldwin RL. How Hofmeister ion interactions affect protein stability. Biophys J. 1996;71:2056–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Parsons DF, Boström M, Nostro P, Lo, Ninham BW. Hofmeister effects: interplay of hydration, nonelectrostatic potentials, and ion size. Phys Chem Chem Phys. 2011;13:12352–67.

    Article  CAS  PubMed  Google Scholar 

  28. Mazzini V, Craig VSJ. What is the fundamental ion-specific series for anions and cations? Ion specificity in standard partial molar volumes of electrolytes and electrostriction in water and non-aqueous solvents. Chem Sci. 2017;8:7052–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ma G, Ji F, Lin W, Chen S. Determination of non-freezing water in different nonfouling materials by differential scanning calorimetry. J Biomater Sci Polym Ed. 2022;33:1012–24.

    Article  CAS  PubMed  Google Scholar 

  30. Leng C, Sun S, Zhang K, Jiang S, Chen Z. Molecular level studies on interfacial hydration of zwitterionic and other antifouling polymers in situ. Acta Biomater. 2016;40:6–15.

    Article  CAS  PubMed  Google Scholar 

  31. Wu J, Lin W, Wang Z, Chen S, Chang Y. Investigation of the hydration of nonfouling material poly(sulfobetaine methacrylate) by low-field nuclear magnetic resonance. Langmuir. 2012;28:7436–41.

    Article  CAS  PubMed  Google Scholar 

  32. Higuchi Y, Saleh MA, Anada T, Tanaka M, Hishida M. Rotational Dynamics of Water near Osmolytes by Molecular Dynamics Simulations. J Phys Chem B. 2024;128:5017.

    Article  Google Scholar 

  33. Meng EC, Kollman PA. Molecular dynamics studies of the properties of water around simple organic solutes. J Phys Chem. 1996;100:11460–70.

    Article  CAS  Google Scholar 

  34. Stirnemann G, Duboué-Dijon E, Laage D. Ab Initio Simulations of Water Dynamics in Aqueous TMAO Solutions: Temperature and Concentration Effects. J Phys Chem B. 2017;121:11189–97.

    Article  CAS  PubMed  Google Scholar 

  35. Saladino G, Marenchino M, Pieraccini S, Campos-Olivas R, Sironi M, Gervasio FL. A simple mechanism underlying the effect of protecting osmolytes on protein folding. J Chem Theory Comput. 2011;7:3846–52.

    Article  CAS  PubMed  Google Scholar 

  36. Usui K, Hunger J, Sulpizi M, Ohto T, Bonn M, Nagata Y. Ab Initio Liquid Water Dynamics in Aqueous TMAO Solution. J Phys Chem B. 2015;119:10597–606.

    Article  CAS  PubMed  Google Scholar 

  37. Hower JC, He Y, Bernards MT, Jiang S. Understanding the nonfouling mechanism of surfaces through molecular simulations of sugar-based self-assembled monolayers. J Chem Phys. 2006;125:214704.

    Article  PubMed  Google Scholar 

  38. Kuo AT, Urata S, Koguchi R, Yamamoto K, Tanaka M. Analyses of equilibrium water content and blood compatibility for Poly(2-methoxyethyl acrylate) by molecular dynamics simulation. Polymer (Guildf). 2019;170:76–84.

    Article  CAS  Google Scholar 

  39. Kuo AT, Sonoda T, Urata S, Koguchi R, Kobayashi S, Tanaka M. Elucidating the Feature of Intermediate Water in Hydrated Poly(ω-methoxyalkyl acrylate)s by Molecular Dynamics Simulation and Differential Scanning Calorimetry Measurement. ACS Biomater Sci Eng. 2020;6:3915–24.

    Article  CAS  PubMed  Google Scholar 

  40. Shikata K, Kikutsuji T, Yasoshima N, Kim K, Matubayasi N. Revealing the hidden dynamics of confined water in acrylate polymers: Insights from hydrogen-bond lifetime analysis. J Chem Phys. 2023;158:174901.

    Article  CAS  PubMed  Google Scholar 

  41. Kuo AT, Urata S, Koguchi R, Sonoda T, Kobayashi S, Tanaka M. Molecular Dynamics Study on the Water Mobility and Side-Chain Flexibility of Hydrated Poly(ω-methoxyalkyl acrylate)s. ACS Biomater Sci Eng. 2020;6:6690–700.

    Article  CAS  PubMed  Google Scholar 

  42. Yang C, Lu D, Liu Z. How PEGylation enhances the stability and potency of insulin: A molecular dynamics simulation. Biochemistry. 2011;50:2585–93.

    Article  CAS  PubMed  Google Scholar 

  43. Martinez L, Andrade R, Birgin EG, Martínez JM. PACKMOL: A package for building initial configurations for molecular dynamics simulations. J Comput Chem. 2009;30:2157–64.

    Article  CAS  PubMed  Google Scholar 

  44. Hourahine B, Aradi B, Blum V, Bonafé F, Buccheri A, Camacho C, et al. DFTB+, a software package for efficient approximate density functional theory based atomistic simulations. J Chem Phys. 2020;152:124101.

    Article  CAS  PubMed  Google Scholar 

  45. Gaus M, Goez A, Elstner M. Parametrization and benchmark of DFTB3 for organic molecules. J Chem Theory Comput. 2013;9:338–54.

    Article  CAS  PubMed  Google Scholar 

  46. Kubillus M, Kubař T, Gaus M, Řezáč J, Elstner M. Parameterization of the DFTB3 method for Br, Ca, Cl, F, I, K, and Na in organic and biological systems. J Chem Theory Comput. 2015;11:332–42.

    Article  CAS  PubMed  Google Scholar 

  47. Goyal P, Qian H-J, Irle S, Lu X, Roston D, Mori T, et al. Molecular simulation of water and hydration effects in different environments: Challenges and developments for DFTB based models. J Phys Chem B. 2014;118:11007–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Řezáč J. Empirical Self-Consistent Correction for the Description of Hydrogen Bonds in DFTB3. J Chem Theory Comput. 2017;13:4804–17.

    Article  PubMed  Google Scholar 

  49. Sakti AW, Nishimura Y, Nakai H. Divide-and-conquer-type density-functional tight-binding simulations of hydroxide ion diffusion in bulk water. J Phys Chem B. 2017;121:1362–71.

    Article  CAS  PubMed  Google Scholar 

  50. Choi TH, Liang R, Maupin CM, Voth GA. Application of the SCC-DFTB method to hydroxide water clusters and aqueous hydroxide solutions. J Phys Chem B. 2013;117:5165–79.

    Article  CAS  PubMed  Google Scholar 

  51. Higuchi Y, Asano Y, Kuwahara T, Hishida M. Rotational Dynamics of Water at the Phospholipid Bilayer Depending on the Head Groups Studied by Molecular Dynamics Simulations. Langmuir. 2021;37:5329–38.

    Article  CAS  PubMed  Google Scholar 

  52. Abascal JLF, Vega C. A general purpose model for the condensed phases of water: TIP4P/2005. J Chem Phys. 2005;123:234505.

  53. Martyna GJ, Tuckerman ME, Tobias DJ, Klein ML. Explicit reversible integrators for extended systems dynamics. Mol Phys. 1996;87:1117–57.

    Article  CAS  Google Scholar 

  54. Berendsen H, Postma J, Van Gunsteren W, DiNola A, Haak J. Molecular dynamics with coupling to an external bath. J Phys Chem. 1984;81:3684–90.

    Article  CAS  Google Scholar 

  55. Martí J, Padro JA, Guàrdia E. Molecular dynamics simulation of liquid water along the coexistence curve: Hydrogen bonds and vibrational spectra. J Chem Phys. 1996;105:639–49.

    Article  Google Scholar 

  56. Hatakeyama H, Hatakeyama T. Interaction between water and hydrophilic polymers. Thermochim Acta. 1998;308:3–22.

    Article  CAS  Google Scholar 

  57. Tanaka M, Hayashi T, Morita S. The roles of water molecules at the biointerface of medical polymers. Polym J. 2013;45:701–10.

    Article  CAS  Google Scholar 

  58. Tanaka M, Motomura T, Ishii N, Shimura K, Onishi M, Mochizuki A, et al. Cold crystallization of water in hydrated poly (2-methoxyethyl acrylate)(PMEA). Polym Int. 2000;49:1709–13.

    Article  CAS  Google Scholar 

  59. Shiomoto S, Inoue K, Higuchi H, Nishimura SN, Takaba H, Tanaka M, et al. Characterization of Hydration Water Bound to Choline Phosphate-Containing Polymers. Biomacromolecules. 2022;23:2999–3008.

    Article  CAS  PubMed  Google Scholar 

  60. Hishida M, Tanaka K. Long-range hydration effect of lipid membrane studied by terahertz time-domain spectroscopy. Phys Rev Lett. 2011;106:158102.

  61. Das N, Tarif E, Dutta A, Sen P. Associated Water Dynamics Might Be a Key Factor Affecting Protein Stability in the Crowded Milieu. J Phys Chem B. 2023;127:3151–63.

    Article  CAS  PubMed  Google Scholar 

  62. Negi KS, Das N, Khan T, Sen P. Osmolyte induced protein stabilization: modulation of associated water dynamics might be a key factor. Phys Chem Chem Phys. 2023;25:32602–12.

    Article  CAS  PubMed  Google Scholar 

  63. Hishida M, Kaneko A, Yamamura Y, Saito K. Contrasting Changes in Strongly and Weakly Bound Hydration Water of a Protein upon Denaturation. J Phys Chem B. 2023;127:6296–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Privalov PL, Makhatadze GI. Contribution of hydration to protein folding thermodynamics: II. The entropy and gibbs energy of hydration. J Mol Biol. 1993;232:660–79.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to the Japanese government (MEXT) for providing a scholarship to pursue higher education and research at Kyushu University. This research was partially supported by JSPS KAKENHI (Grant Numbers JP19H05717, JP19H05718, JP19H05720, and JP22H00591). We thank the Supercomputer Center at the Institute for Solid–State Physics, University of Tokyo, for the use of its facilities. We also thank the Cooperative Research Program “Dynamic Alliance for Open Innovation Bridging Human, Environment, and Materials” for their support.

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Authors and Affiliations

  1. Department of Applied Chemistry, Graduate School of Engineering, Kyushu University, Fukuoka, Japan

    Md Abu Saleh, Takahisa Anada & Masaru Tanaka

  2. Research Institute for Information Technology, Kyushu University, Fukuoka, Japan

    Yuji Higuchi

  3. Institute for Materials Chemistry and Engineering, Kyushu University, Fukuoka, Japan

    Shohei Shiomoto, Takahisa Anada & Masaru Tanaka

  4. Department of Chemistry, Faculty of Science, Tokyo University of Science, Tokyo, Japan

    Mafumi Hishida

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Correspondence to Yuji Higuchi or Masaru Tanaka.

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Saleh, M.A., Higuchi, Y., Shiomoto, S. et al. Effect of zwitterionic monomer polymerization on water dynamics: a molecular dynamics simulation study supported by differential scanning calorimetry and terahertz spectroscopy. Polym J 57, 1127–1139 (2025). https://doi.org/10.1038/s41428-025-01066-0

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