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.

CEITEC─Central European Institute of Technology Masaryk University Kamenice 753 5 CZ 62500 Brno Czech Republic

Department of Physical Chemistry University of Chemistry and Technology Prague Technická 5 CZ 166 28 Prague 6 Czech Republic

Division of Pharmaceutical Biosciences Faculty of Pharmacy University of Helsinki Viikinkaari 5 FI 00790 Helsinki Finland

Institute of Biotechnology University of Helsinki Viikinkaari 5 FI 00790 Helsinki Finland

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Flemingovo nám 2 CZ 160 00 Prague 6 Czech Republic

National Centre for Biomolecular Research Faculty of Science Masaryk University Kamenice 753 5 CZ 62500 Brno Czech Republic

VTT Technical Research Centre of Finland Tietotie 2 FI 02150 Espoo Finland

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Dror R. O.; Dirks R. M.; Grossman J.; Xu H.; Shaw D. E. Biomolecular Simulation: A Computational Microscope for Molecular Biology. Annu. Rev. Biophys. 2012, 41, 429–452. 10.1146/annurev-biophys-042910-155245. PubMed DOI

Van der Spoel D. Systematic Design of Biomolecular Force Fields. Curr. Opin. Struct. Biol. 2021, 67, 18–24. 10.1016/j.sbi.2020.08.006. PubMed DOI

Dauber-Osguthorpe P.; Hagler A. T. Biomolecular Force Fields: Where Have We Been, Where Are We Now, Where Do We Need to Go and How Do We Get There?. J. Comput. Aided Mol. Des. 2019, 33, 133–203. 10.1007/s10822-018-0111-4. PubMed DOI

Nerenberg P. S.; Head-Gordon T. New Developments in Force Fields for Biomolecular Simulations. Curr. Opin. Struct. Biol. 2018, 49, 129–138. 10.1016/j.sbi.2018.02.002. PubMed DOI

Antila H. S.; Kav B.; Miettinen M. S.; Martinez-Seara H.; Jungwirth P.; Ollila O. H. S. Emerging Era of Biomolecular Membrane Simulations: Automated Physically-Justified Force Field Development and Quality-Evaluated Databanks. J. Phys. Chem. B 2022, 126, 4169–4183. 10.1021/acs.jpcb.2c01954. DOI

Kiirikki A.; Antila H. S.; Bort L. S.; Buslaev P.; Favela-Rosales F.; Ferreira T. M.; Fuchs P. F.; Garcia-Fandino R.; Gushchin I.; Kav B.; Kučerka N.; Kula P.; Kurki M.; Kuzmin A.; Lalitha A.; Lolicato F.; Madsen J. J.; Miettinen M. S.; Mingham C.; Monticelli L.; Nencini R.; Nesterenko A. M.; J P. T.; Piñeiro A.; Reuter N.; Samantray S.; Suárez-Lestón F.; Talandashti R.; Ollila O. S. NMRlipids Databank Makes Data-Driven Analysis of Biomembrane Properties Accessible for All. Nat. Commun. 2024, 15, 1136.10.1038/s41467-024-45189-z. PubMed DOI PMC

Clapham D. E. Calcium Signaling. Cell 1995, 80, 259–268. 10.1016/0092-8674(95)90408-5. PubMed DOI

Bosshard H. R.; Marti D. N.; Jelesarov I. Protein Stabilization by Salt Bridges: Concepts, Experimental Approaches and Clarification of Some Misunderstandings. J. Mol. Recognit. 2004, 17, 1–16. 10.1002/jmr.657. PubMed DOI

Andreini C.; Bertini I.; Cavallaro G.; Holliday G. L.; Thornton J. M. Metal Ions in Biological Catalysis: From Enzyme Databases to General Principles. J. Biol. Inorg. Chem. 2008, 13, 1205–1218. 10.1007/s00775-008-0404-5. PubMed DOI

Lemmon M. A. Membrane Recognition by Phospholipid-Binding Domains. Nat. Rev. Mol. Cell Biol. 2008, 9, 99–111. 10.1038/nrm2328. PubMed DOI

Herman C. E.; Valiya Parambathu A.; Asthagiri D. N.; Lenhoff A. M. Polarizability Plays a Decisive Role in Modulating Association Between Molecular Cations and Anions. J. Phys. Chem. Lett. 2023, 14, 7020–7026. 10.1021/acs.jpclett.3c01566. PubMed DOI

Marrink S. J.; Berendsen H. J. Permeation Process of Small Molecules Across Lipid Membranes Studied by Molecular Dynamics Simulations. J. Phys. Chem. 1996, 100, 16729–16738. 10.1021/jp952956f. DOI

Simonson T.; Brooks C. L. Charge Screening and the Dielectric Constant of Proteins: Insights From Molecular Dynamics. J. Am. Chem. Soc. 1996, 118, 8452–8458. 10.1021/ja960884f. DOI

Kohagen M.; Mason P. E.; Jungwirth P. Accounting for Electronic Polarization Effects in Aqueous Sodium Chloride via Molecular Dynamics Aided by Neutron Scattering. J. Phys. Chem. B 2016, 120, 1454–1460. 10.1021/acs.jpcb.5b05221. PubMed DOI

Martinek T.; Duboué-Dijon E.; Timr S. ˇ.; Mason P. E.; Baxová K.; Fischer H. E.; Schmidt B.; Pluhařová E.; Jungwirth P. Calcium Ions in Aqueous Solutions: Accurate Force Field Description Aided by Ab Initio Molecular Dynamics and Neutron Scattering. J. Chem. Phys. 2018, 148, 222813.10.1063/1.5006779. PubMed DOI

Pluhařová E.; Fischer H. E.; Mason P. E.; Jungwirth P. Hydration of the Chloride Ion in Concentrated Aqueous Solutions Using Neutron Scattering and Molecular Dynamics. Mol. Phys. 2014, 112, 1230–1240. 10.1080/00268976.2013.875231. DOI

Catte A.; Girych M.; Javanainen M.; Loison C.; Melcr J.; Miettinen M. S.; Monticelli L.; Määttä J.; Oganesyan V. S.; Ollila O. H. S.; Tynkkynen J.; Vilov S. Molecular Electrometer and Binding of Cations to Phospholipid Bilayers. Phys. Chem. Chem. Phys. 2016, 18, 32560–32569. 10.1039/C6CP04883H. PubMed DOI

Antila H.; Buslaev P.; Favela-Rosales F.; Ferreira T. M.; Gushchin I.; Javanainen M.; Kav B.; Madsen J. J.; Melcr J.; Miettinen M. S.; Määttä J.; Nencini R.; Ollila O. H. S.; Piggot T. J. Headgroup Structure and Cation Binding in Phosphatidylserine Lipid Bilayers. J. Phys. Chem. B 2019, 123, 9066–9079. 10.1021/acs.jpcb.9b06091. PubMed DOI

Andrews C. T.; Elcock A. H. Molecular Dynamics Simulations of Highly Crowded Amino Acid Solutions: Comparisons of Eight Different Force Field Combinations With Experiment and With Each Other. J. Chem. Theory Comput. 2013, 9, 4585–4602. 10.1021/ct400371h. PubMed DOI PMC

Miller M. S.; Lay W. K.; Li S.; Hacker W. C.; An J.; Ren J.; Elcock A. H. Reparametrization of Protein Force Field Nonbonded Interactions Guided by Osmotic Coefficient Measurements From Molecular Dynamics Simulations. J. Chem. Theory Comput. 2017, 13, 1812–1826. 10.1021/acs.jctc.6b01059. PubMed DOI PMC

Miller M. S.; Lay W. K.; Elcock A. H. Osmotic Pressure Simulations of Amino Acids and Peptides Highlight Potential Routes to Protein Force Field Parameterization. J. Phys. Chem. B 2016, 120, 8217–8229. 10.1021/acs.jpcb.6b01902. PubMed DOI PMC

Riopedre-Fernandez M.; Biriukov D.; Dračínský M.; Martinez-Seara H. Hyaluronan-Arginine Enhanced and Dynamic Interaction Emerges From Distinctive Molecular Signature Due to Electrostatics and Side-Chain Specificity. Carbohydr. Polym. 2024, 325, 121568.10.1016/j.carbpol.2023.121568. PubMed DOI

Shaw D. E.; Dror R. O.; Salmon J. K.; Grossman J. P.; Mackenzie K. M.; Bank J. A.; Young C.; Deneroff M. M.; Batson B.; Bowers K. J.; Chow E.; Eastwood M. P.; Ierardi D. J.; Klepeis J. L.; Kuskin J. S.; Larson R. H.; Lindorff-Larsen K.; Maragakis P.; Moraes M. A.; Piana S.; Shan Y.; Towles B.. Millisecond-Scale Molecular Dynamics Simulations on Anton. Proceedings of the Conference on High Performance Computing Networking, Storage and Analysis; Association for Computing Machinery, 2009.

Duboue-Dijon E.; Javanainen M.; Delcroix P.; Jungwirth P.; Martinez-Seara H. A Practical Guide to Biologically Relevant Molecular Simulations With Charge Scaling for Electronic Polarization. J. Chem. Phys. 2020, 153, 050901.10.1063/5.0017775. PubMed DOI

Leontyev I. V.; Stuchebrukhov A. A. Electronic Continuum Model for Molecular Dynamics Simulations. J. Chem. Phys. 2009, 130, 130.10.1063/1.3060164. PubMed DOI PMC

Kohagen M.; Lepšík M.; Jungwirth P. Calcium Binding to Calmodulin by Molecular Dynamics With Effective Polarization. J. Phys. Chem. Lett. 2014, 5, 3964–3969. 10.1021/jz502099g. PubMed DOI

Ponder J. W.; Wu C.; Ren P.; Pande V. S.; Chodera J. D.; Schnieders M. J.; Haque I.; Mobley D. L.; Lambrecht D. S.; DiStasio R. A.; Head-Gordon M.; Clark G. N. I.; Johnson M. E.; Head-Gordon T. Current Status of the AMOEBA Polarizable Force Field. J. Phys. Chem. B 2010, 114, 2549–2564. 10.1021/jp910674d. PubMed DOI PMC

Patel S.; Brooks C. L. Fluctuating Charge Force Fields: Recent Developments and Applications From Small Molecules to Macromolecular Biological Systems. Mol. Simul. 2006, 32, 231–249. 10.1080/08927020600726708. DOI

Lamoureux G.; Roux B. Modeling Induced Polarization With Classical Drude Oscillators: Theory and Molecular Dynamics Simulation Algorithm. J. Chem. Phys. 2003, 119, 3025–3039. 10.1063/1.1589749. DOI

Li H.; Chowdhary J.; Huang L.; He X.; MacKerell A. D.; Roux B. Drude Polarizable Force Field for Molecular Dynamics Simulations of Saturated and Unsaturated Zwitterionic Lipids. J. Chem. Theory Comput. 2017, 13, 4535–4552. 10.1021/acs.jctc.7b00262. PubMed DOI PMC

Antila H. S.; Dixit S.; Kav B.; Madsen J. J.; Miettinen M. S.; Ollila O. H. S. Evaluating Polarizable Biomembrane Simulations against Experiments. J. Chem. Theory Comput. 2024, 20, 4325–4337. 10.1021/acs.jctc.3c01333. PubMed DOI PMC

Han K.; Venable R. M.; Bryant A.-M.; Legacy C. J.; Shen R.; Li H.; Roux B.; Gericke A.; Pastor R. W. Graph-Theoretic Analysis of Monomethyl Phosphate Clustering in Ionic Solutions. J. Phys. Chem. B 2018, 122, 1484–1494. 10.1021/acs.jpcb.7b10730. PubMed DOI PMC

Leontyev I.; Stuchebrukhov A. Electronic Continuum Model for Molecular Dynamics Simulations. J. Chem. Phys. 2009, 130, 02B609.10.1063/1.3060164. PubMed DOI PMC

Leontyev I.; Stuchebrukhov A. Accounting for Electronic Polarization in Non-polarizable Force Fields. Phys. Chem. Chem. Phys. 2011, 13, 2613–2626. 10.1039/c0cp01971b. PubMed DOI

Kirby B. J.; Jungwirth P. Charge Scaling Manifesto: A Way of Reconciling the Inherently Macroscopic and Microscopic Natures of Molecular Simulations. J. Phys. Chem. Lett. 2019, 10, 7531–7536. 10.1021/acs.jpclett.9b02652. PubMed DOI

Kohagen M.; Mason P. E.; Jungwirth P. Accurate Description of Calcium Solvation in Concentrated Aqueous Solutions. J. Phys. Chem. B 2014, 118, 7902–7909. 10.1021/jp5005693. PubMed DOI

Nencini R.; Ollila O. H. S. Charged Small Molecule Binding to Membranes in MD Simulations Evaluated against NMR Experiments. J. Phys. Chem. B 2022, 126, 6955–6963. 10.1021/acs.jpcb.2c05024. PubMed DOI PMC

Biriukov D.; Wang H. W.; Rampal N.; Tempra C.; Kula P.; Neuefeind J. C.; Stack A. G.; Předota M. The “Good,” the “Bad,” and the “Hidden”’ in Neutron Scattering and Molecular Dynamics of Ionic Aqueous Solutions. J. Chem. Phys. 2022, 156, 194505.10.1063/5.0093643. PubMed DOI

Tolmachev D.; Boyko O.; Lukasheva N.; Martinez-Seara H.; Karttunen M. Overbinding and Qualitative and Quantitative Changes Caused by Simple Na+ and K+ Ions in Polyelectrolyte Simulations: Comparison of Force Fields With and Without NBFIX and Ecc Corrections. J. Chem. Theory Comput. 2020, 16, 677–687. 10.1021/acs.jctc.9b00813. PubMed DOI

Duboué-Dijon E.; Delcroix P.; Martinez-Seara H.; Hladílková J.; Coufal P.; Křížek T.; Jungwirth P. Binding of Divalent Cations to Insulin: Capillary Electrophoresis and Molecular Simulations. J. Phys. Chem. B 2018, 122, 5640–5648. 10.1021/acs.jpcb.7b12097. PubMed DOI

Melcr J.; Martinez-Seara H.; Nencini R.; Kolafa J.; Jungwirth P.; Ollila O. H. S. Accurate Binding of Sodium and Calcium to a POPC Bilayer by Effective Inclusion of Electronic Polarization. J. Phys. Chem. B 2018, 122, 4546–4557. 10.1021/acs.jpcb.7b12510. PubMed DOI

Melcr J.; Ferreira T. M.; Jungwirth P.; Ollila O. H. S. Improved Cation Binding to Lipid Bilayers With Negatively Charged POPS by Effective Inclusion of Electronic Polarization. J. Chem. Theory Comput. 2020, 16, 738–748. 10.1021/acs.jctc.9b00824. PubMed DOI

Bacle A.; Buslaev P.; Garcia-Fandino R.; Favela-Rosales F.; Mendes Ferreira T.; Fuchs P. F.; Gushchin I.; Javanainen M.; Kiirikki A. M.; Madsen J. J.; Melcr J.; Milán Rodríguez P.; Miettinen M. S.; Ollila O. H. S.; Papadopoulos C. G.; Peón A.; Piggot T. J.; Piñeiro Á.; Virtanen S. I. Inverse Conformational Selection in Lipid–Protein Binding. J. Am. Chem. Soc. 2021, 143, 13701–13709. 10.1021/jacs.1c05549. PubMed DOI

Zeron I. M.; Abascal J. L. F.; Vega C. A Force Field of Li+, Na+, K+, Mg2+, Ca2+, Cl–, and SO 42-In Aqueous Solution Based on the TIP4P/2005 Water Model and Scaled Charges for the Ions. J. Chem. Phys. 2019, 151, 134504.10.1063/1.5121392. PubMed DOI

Blazquez S.; Conde M.; Abascal J.; Vega C. The Madrid–2019 Force Field for Electrolytes in Water Using TIP4P/2005 and Scaled Charges: Extension to the Ions F–, Br–, I–, Rb+, and Cs+. J. Chem. Phys. 2022, 156, 156.10.1063/5.0077716. PubMed DOI

Biriukov D.; Kroutil O.; Kabeláč M.; Ridley M. K.; MacHesky M. L.; Předota M. Oxalic Acid Adsorption on Rutile: Molecular Dynamics and ab Initio Calculations. Langmuir 2019, 35, 7617–7630. 10.1021/acs.langmuir.8b03984. PubMed DOI

Marchioro A.; Bischoff M.; Lütgebaucks C.; Biriukov D.; Předota M.; Roke S. Surface Characterization of Colloidal Silica Nanoparticles by Second Harmonic Scattering: Quantifying the Surface Potential and Interfacial Water Order. J. Phys. Chem. C 2019, 123, 20393–20404. 10.1021/acs.jpcc.9b05482. PubMed DOI PMC

Biriukov D.; Kroutil O.; Předota M. Modeling of Solid–Liquid Interfaces Using Scaled Charges: Rutile (110) Surfaces. Phys. Chem. Chem. Phys. 2018, 20, 23954–23966. 10.1039/C8CP04535F. PubMed DOI

Biriukov D.; Fibich P.; Předota M. Zeta Potential Determination From Molecular Simulations. J. Phys. Chem. C 2020, 124, 3159–3170. 10.1021/acs.jpcc.9b11371. DOI

Phan L. X.; Chamorro V. C.; Martinez-Seara H.; Crain J.; Sansom M.; Tucker S. J. Influence of Electronic Polarization on the Binding of Anions to a Chloride-Pumping Rhodopsin. Biophys. J. 2023, 122, 1548–1556. 10.1016/j.bpj.2023.03.026. PubMed DOI PMC

Schröder C. Comparing Reduced Partial Charge Models With Polarizable Simulations of Ionic Liquids. Phys. Chem. Chem. Phys. 2012, 14, 3089–3102. 10.1039/c2cp23329k. PubMed DOI PMC

Pal T.; Vogel M. On the Relevance of Electrostatic Interactions for the Structural Relaxation of Ionic Liquids: A Molecular Dynamics Simulation Study. J. Chem. Phys. 2019, 150, 124501.10.1063/1.5085508. PubMed DOI

Chaumont A.; Schurhammer R.; Wipff G. Aqueous Interfaces With Hydrophobic Room-Temperature Ionic Liquids: A Molecular Dynamics Study. J. Phys. Chem. B 2005, 109, 18964–18973. 10.1021/jp052854h. PubMed DOI

Předota M.; Biriukov D. Electronic Continuum Correction Without Scaled Charges. J. Mol. Liq. 2020, 314, 113571.10.1016/j.molliq.2020.113571. DOI

Melcr J.; Piquemal J.-P. Accurate Biomolecular Simulations Account for Electronic Polarization. Front. Mol. Biosci. 2019, 6, 143.10.3389/fmolb.2019.00143. PubMed DOI PMC

Huang J.; Rauscher S.; Nawrocki G.; Ran T.; Feig M.; de Groot B. L.; Grubmüller H.; MacKerell A. D. CHARMM36m: An Improved Force Field for Folded and Intrinsically Disordered Proteins. Nat. Methods 2017, 14, 71–73. 10.1038/nmeth.4067. PubMed DOI PMC

Virtanen S. I.; Kiirikki A. M.; Mikula K. M.; Iwaï H.; Ollila O. H. S. Heterogeneous Dynamics in Partially Disordered Proteins. Phys. Chem. Chem. Phys. 2020, 22, 21185–21196. 10.1039/D0CP03473H. PubMed DOI

Robustelli P.; Piana S.; Shaw D. E. Developing a Molecular Dynamics Force Field for Both Folded and Disordered Protein States. Proc. Natl. Acad. Sci. U.S.A. 2018, 115, 115.10.1073/pnas.1800690115. PubMed DOI PMC

Klauda J. B.; Venable R. M.; Freites J. A.; O’Connor J. W.; Tobias D. J.; Mondragon-Ramirez C.; Vorobyov I.; MacKerell A. D.; Pastor R. W. Update of the CHARMM All-Atom Additive Force Field for Lipids: Validation on Six Lipid Types. J. Phys. Chem. B 2010, 114, 7830–7843. 10.1021/jp101759q. PubMed DOI PMC

Venable R. M.; Luo Y.; Gawrisch K.; Roux B.; Pastor R. W. Simulations of Anionic Lipid Membranes: Development of Interaction-Specific Ion Parameters and Validation Using NMR Data. J. Phys. Chem. B 2013, 117, 10183–10192. 10.1021/jp401512z. PubMed DOI PMC

Guvench O.; Hatcher E.; Venable R. M.; Pastor R. W.; MacKerell A. D. CHARMM Additive All-Atom Force Field for Glycosidic Linkages Between Hexopyranoses. J. Chem. Theory Comput. 2009, 5, 2353–2370. 10.1021/ct900242e. PubMed DOI PMC

Guvench O.; Mallajosyula S. S.; Raman E. P.; Hatcher E.; Vanommeslaeghe K.; Foster T. J.; Jamison F. W.; MacKerell A. D. CHARMM Additive All-Atom Force Field for Carbohydrate Derivatives and Its Utility in Polysaccharide and Carbohydrate–Protein Modeling. J. Chem. Theory Comput. 2011, 7, 3162–3180. 10.1021/ct200328p. PubMed DOI PMC

Lee J.; Cheng X.; Swails J. M.; Yeom M. S.; Eastman P. K.; Lemkul J. A.; Wei S.; Buckner J.; Jeong J. C.; Qi Y.; Jo S.; Pande V. S.; Case D. A.; Brooks C. L.; MacKerell A. D. J.; Klauda J. B.; Im W. CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field. J. Chem. Theory Comput. 2016, 12, 405–413. 10.1021/acs.jctc.5b00935. PubMed DOI PMC

Nosé S. A Molecular Dynamics Method for Simulations in the Canonical Ensemble. Mol. Phys. 1984, 52, 255–268. 10.1080/00268978400101201. DOI

Hoover W. G. Canonical Dynamics: Equilibrium Phase-Space Distributions. Phys. Rev. A 1985, 31, 1695–1697. 10.1103/PhysRevA.31.1695. PubMed DOI

Parrinello M.; Rahman A. Polymorphic Transitions in Single Crystals: A New Molecular Dynamics Method. J. Appl. Phys. 1981, 52, 7182–7190. 10.1063/1.328693. DOI

Essmann U.; Perera L.; Berkowitz M. L.; Darden T.; Lee H.; Pedersen L. G. A Smooth Particle Mesh Ewald Method. J. Chem. Phys. 1995, 103, 8577–8593. 10.1063/1.470117. DOI

Steinbach P. J.; Brooks B. R. New Spherical-Cutoff Methods for Long-Range Forces in Macromolecular Simulation. J. Comput. Chem. 1994, 15, 667–683. 10.1002/jcc.540150702. DOI

Páll S.; Hess B. A Flexible Algorithm for Calculating Pair Interactions on SIMD Architectures. Comput. Phys. Commun. 2013, 184, 2641–2650. 10.1016/j.cpc.2013.06.003. DOI

Miyamoto S.; Kollman P. A. Settle: An Analytical Version of the SHAKE and RATTLE Algorithm for Rigid Water Models. J. Comput. Chem. 1992, 13, 952–962. 10.1002/jcc.540130805. DOI

Hess B.; Bekker H.; Berendsen H. J. C.; Fraaije J. G. E. M. LINCS A Linear Constraint Solver for Molecular Simulations. J. Comput. Chem. 1997, 18, 1463–1472. 10.1002/(sici)1096-987x(199709)18:12<1463::aid-jcc4>3.3.co;2-l. DOI

Hess B. P-LINCS A Parallel Linear Constraint Solver for Molecular Simulation. J. Chem. Theory Comput. 2008, 4, 116–122. 10.1021/ct700200b. PubMed DOI

MacKerell A. D.; Bashford D.; Bellott M.; Dunbrack R. L.; Evanseck J. D.; Field M. J.; Fischer S.; Gao J.; Guo H.; Ha S.; Joseph-McCarthy D.; Kuchnir L.; Kuczera K.; Lau F. T. K.; Mattos C.; Michnick S.; Ngo T.; Nguyen D. T.; Prodhom B.; Reiher W. E.; Roux B.; Schlenkrich M.; Smith J. C.; Stote R.; Straub J.; Watanabe M.; Wiórkiewicz-Kuczera J.; Yin D.; Karplus M. All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of Proteins. J. Phys. Chem. B 1998, 102, 3586–3616. 10.1021/jp973084f. PubMed DOI

Durell S. R.; Brooks B. R.; Ben-Naim A. Solvent-Induced Forces Between Two Hydrophilic Groups. J. Phys. Chem. 1994, 98, 2198–2202. 10.1021/j100059a038. DOI

Luo Y.; Roux B. Simulation of Osmotic Pressure in Concentrated Aqueous Salt Solutions. J. Phys. Chem. Lett. 2010, 1, 183–189. 10.1021/jz900079w. DOI

Lay W. K.; Miller M. S.; Elcock A. H. Optimizing Solute-Solute Interactions in the GLYCAM06 and CHARMM36 Carbohydrate Force Fields Using Osmotic Pressure Measurements. J. Chem. Theory Comput. 2016, 12, 1401–1407. 10.1021/acs.jctc.5b01136. PubMed DOI PMC

Lay W. K.; Miller M. S.; Elcock A. H. Reparameterization of Solute-Solute Interactions for Amino Acid–Sugar Systems Using Isopiestic Osmotic Pressure Molecular Dynamics Simulations. J. Chem. Theory Comput. 2017, 13, 1874–1882. 10.1021/acs.jctc.7b00194. PubMed DOI PMC

Ollila O. S.; Pabst G. Atomistic Resolution Structure and Dynamics of Lipid Bilayers in Simulations and Experiments. Biochim. Biophys. Acta 2016, 1858, 2512–2528. 10.1016/j.bbamem.2016.01.019. PubMed DOI

Botan A.; Favela-Rosales F.; Fuchs P. F.; Javanainen M.; Kanduč M.; Kulig W.; Lamberg A.; Loison C.; Lyubartsev A.; Miettinen M. S.; Monticelli L.; Määttä J.; Ollila O. H. S.; Retegan M.; Rog T.; Santuz H.; Tynkkynen J. Toward Atomistic Resolution Structure of Phosphatidylcholine Headgroup and Glycerol Backbone at Different Ambient Conditions. J. Phys. Chem. B 2015, 119, 15075–15088. 10.1021/acs.jpcb.5b04878. PubMed DOI PMC

Ferreira T. M.; Coreta-Gomes F.; Ollila O. H. S.; Moreno M. J.; Vaz W. L.; Topgaard D. Cholesterol and POPC Segmental Order Parameters in Lipid Membranes: Solid State 1H–13C NMR and MD Simulation Studies. Phys. Chem. Chem. Phys. 2013, 15, 1976–1989. 10.1039/C2CP42738A. PubMed DOI

Seelig J.; MacDonald P. M.; Scherer P. G. Phospholipid Head Groups as Sensors of Electric Charge in Membranes. Biochemistry 1987, 26, 7535–7541. 10.1021/bi00398a001. PubMed DOI

Altenbach C.; Seelig J. Calcium Binding to Phosphatidylcholine Bilayers as Studied by Deuterium Magnetic Resonance. Evidence for the Formation of a Calcium Complex With Two Phospholipid Molecules. Biochemistry 1984, 23, 3913–3920. 10.1021/bi00312a019. PubMed DOI

Javanainen M.; Melcrová A.; Magarkar A.; Jurkiewicz P.; Hof M.; Jungwirth P.; Martinez-Seara H. Two Cations, Two Mechanisms: Interactions of Sodium and Calcium With Zwitterionic Lipid Membranes. Chem. Commun. 2017, 53, 5380–5383. 10.1039/C7CC02208E. PubMed DOI

Polák J.; Ondo D.; Heyda J. Thermodynamics of N-Isopropylacrylamide in Water: Insight From Experiments, Simulations, and Kirkwood–Buff Analysis Teamwork. J. Phys. Chem. B 2020, 124, 2495–2504. 10.1021/acs.jpcb.0c00413. PubMed DOI

Hervø-Hansen S.; Polák J.; Tomandlová M.; Dzubiella J.; Heyda J.; Lund M. Salt Effects on Caffeine Across Concentration Regimes. J. Phys. Chem. B 2023, 127, 10253–10265. 10.1021/acs.jpcb.3c01085. PubMed DOI PMC

Mason P. E.; Ansell S.; Neilson G. W. Neutron Diffraction Studies of Electrolytes in Null Water: A Direct Determination of the First Hydration Zone of Ions. J. Phys.: Condens. Matter 2006, 18, 8437–8447. 10.1088/0953-8984/18/37/004. PubMed DOI

Van Meer G.; Voelker D. R.; Feigenson G. W. Membrane Lipids: Where They Are and How They Behave. Nat. Rev. Mol. Cell Biol. 2008, 9, 112–124. 10.1038/nrm2330. PubMed DOI PMC

Kim S.; Patel D. S.; Park S.; Slusky J.; Klauda J. B.; Widmalm G.; Im W. Bilayer Properties of Lipid a From Various Gram-Negative Bacteria. Biophys. J. 2016, 111, 1750–1760. 10.1016/j.bpj.2016.09.001. PubMed DOI PMC

Binder H.; Zschörnig O. The Effect of Metal Cations on the Phase Behavior and Hydration Characteristics of Phospholipid Membranes. Chem. Phys. Lipids 2002, 115, 39–61. 10.1016/S0009-3084(02)00005-1. PubMed DOI

Nagarsekar K.; Ashtikar M.; Steiniger F.; Thamm J.; Schacher F.; Fahr A. Understanding Cochleate Formation: Insights Into Structural Development. Soft Matter 2016, 12, 3797–3809. 10.1039/C5SM01469G. PubMed DOI

Roux M.; Bloom M. Ca2+, Mg2+, Li+, Na+, and K+ Distributions in the Headgroup Region of Binary Membranes of Phosphatidylcholine and Phosphatidylserine as Seen by Deuterium NMR. Biochemistry 1990, 29, 7077–7089. 10.1021/bi00482a019. PubMed DOI

Riopedre-Fernandez M.; Kostal V.; Martinek T.; Martinez-Seara H.; Biriukov D. Developing and Benchmarking Sulfate and Sulfamate Force Field Parameters for Glycosaminoglycans via Ab Initio Molecular Dynamics Simulations. bioRxiv 2024, 596767.10.1101/2024.05.31.596767. PubMed DOI

Mason P. E.; Wernersson E.; Jungwirth P. Accurate Description of Aqueous Carbonate Ions: An Effective Polarization Model Verified by Neutron Scattering. J. Phys. Chem. B 2012, 116, 8145–8153. 10.1021/jp3008267. PubMed DOI

Duboué-Dijon E.; Mason P. E.; Fischer H. E.; Jungwirth P. Hydration and Ion Pairing in Aqueous Mg+2 And Zn+2 Solutions: Force-Field Description Aided by Neutron Scattering Experiments and Ab Initio Molecular Dynamics Simulations. J. Phys. Chem. B 2018, 122, 3296–3306. 10.1021/acs.jpcb.7b09612. PubMed DOI

Laliberté M. A Model for Calculating the Heat Capacity of Aqueous Solutions, with Updated Density and Viscosity Data. J. Chem. Eng. Data 2009, 54, 1725–1760. 10.1021/je8008123. DOI

Chatterjee S.; Debenedetti P. G.; Stillinger F. H.; Lynden-Bell R. M. A. A computational investigation of thermodynamics, structure, dynamics and solvation behavior in modified water models. J. Chem. Phys. 2008, 128, 12511.10.1063/1.2841127. PubMed DOI

Lukasheva N.; Tolmachev D.; Martinez-Seara H.; Karttunen M. Changes in the Local Conformational States Caused by Simple Na+ And K+ Ions in Polyelectrolyte Simulations: Comparison of Seven Force Fields With and Without NBFIX and ECC Corrections. Polymers 2022, 14, 252.10.3390/polym14020252. PubMed DOI PMC

Cruces Chamorro V.; Jungwirth P.; Martinez-Seara H. Building Water Models Compatible With Charge Scaling Molecular Dynamics. J. Phys. Chem. Lett. 2024, 15, 2922–2928. 10.1021/acs.jpclett.4c00344. PubMed DOI PMC

Verdaguer N.; Corbalan-Garcia S.; Ochoa W. F.; Fita I.; Gómez-Fernández J. C. Ca2+ Bridges the C2Membrane-Binding Domain of Protein Kinase Cα Directly to Phosphatidylserine. EMBO J. 1999, 18, 6329–6338. 10.1093/emboj/18.22.6329. PubMed DOI PMC

Egberts E.; Marrink S.-J.; Berendsen H. J. Molecular Dynamics Simulation of a Phospholipid Membrane. Eur. Biophys. J. 1994, 22, 423–436. 10.1007/bf00180163. PubMed DOI

Tieleman D. P.; Berendsen H. Molecular Dynamics Simulations of a Fully Hydrated Dipalmitoylphosphatidylcholine Bilayer With Different Macroscopic Boundary Conditions and Parameters. J. Chem. Phys. 1996, 105, 4871–4880. 10.1063/1.472323. DOI

Kostal V.; Jungwirth P.; Martinez-Seara H. Nonaqueous Ion Pairing Exemplifies the Case for Including Electronic Polarization in Molecular Dynamics Simulations. J. Phys. Chem. Lett. 2023, 14, 8691–8696. 10.1021/acs.jpclett.3c02231. PubMed DOI PMC

Free Energy of Membrane Pore Formation and Stability from Molecular Dynamics Simulations

Molecular dynamics simulations unveil the aggregation patterns and salting out of polyarginines at zwitterionic POPC bilayers in solutions of various ionic strengths

Developing and Benchmarking Sulfate and Sulfamate Force Field Parameters via Ab Initio Molecular Dynamics Simulations To Accurately Model Glycosaminoglycan Electrostatic Interactions