Many-body effect determines the selectivity for Ca2+ and Mg2+ in proteins

Significance Metal ions have important biological functions and are associated with diseases including cancer and neurodegenerative disorders. The fundamental question of metal ion selectivity in proteins has received continued interest over the past decades. Compared with Na+/K+, the selectivity for Mg2+/Ca2+ is less well understood. Although Mg2+ is a better charge acceptor, calcium-binding proteins with highly charged binding pockets can selectively bind Ca2+ against a much higher concentration of Mg2+. Here we show that this selectivity is dictated by the many-body polarization effect, which is a cost arising from the dense packing of multiple residues around the metal ion. By combining geometric constraint and the many-body effect, it is possible to fine-tune the selectivity for metal ions of different sizes. Calcium ion is a versatile messenger in many cell-signaling processes. To achieve their functions, calcium-binding proteins selectively bind Ca2+ against a background of competing ions such as Mg2+. The high specificity of calcium-binding proteins has been intriguing since Mg2+ has a higher charge density than Ca2+ and is expected to bind more tightly to the carboxylate groups in calcium-binding pockets. Here, we showed that the specificity for Ca2+ is dictated by the many-body polarization effect, which is an energetic cost arising from the dense packing of multiple residues around the metal ion. Since polarization has stronger distance dependence compared with permanent electrostatics, the cost associated with the smaller Mg2+ is much higher than that with Ca2+ and outweighs the electrostatic attraction favorable for Mg2+. With the AMOEBA (atomic multipole optimized energetics for biomolecular simulation) polarizable force field, our simulations captured the relative binding free energy between Ca2+ and Mg2+ for proteins with various types of binding pockets and explained the nonmonotonic size dependence of the binding free energy in EF-hand proteins. Without electronic polarization, the smaller ions are always favored over larger ions and the relative binding free energy is roughly proportional to the net charge of the pocket. The many-body effect depends on both the number and the arrangement of charged residues. Fine-tuning of the ion selectivity could be achieved by combining the many-body effect and geometric constraint.

[1]  Yifeng Wang,et al.  Natural Indices for the Chemical Hardness/Softness of Metal Cations and Ligands , 2017, ACS omega.

[2]  Pengyu Y. Ren,et al.  Study of interactions between metal ions and protein model compounds by energy decomposition analyses and the AMOEBA force field. , 2017, The Journal of chemical physics.

[3]  K. Raghavachari,et al.  Anion Binding in Solution: Beyond the Electrostatic Regime , 2017 .

[4]  Zhi Wang,et al.  Tinker‐OpenMM: Absolute and relative alchemical free energies using AMOEBA on GPUs , 2017, J. Comput. Chem..

[5]  S. L. Zultanski,et al.  General Principles and Strategies for Salting-Out Informed by the Hofmeister Series , 2017 .

[6]  D. Salahub,et al.  Selective ion binding and transport by membrane proteins – A computational perspective , 2017 .

[7]  Xiao Wang,et al.  Psi4 1.1: An Open-Source Electronic Structure Program Emphasizing Automation, Advanced Libraries, and Interoperability. , 2017, Journal of chemical theory and computation.

[8]  B. Roux.  Ion channels and ion selectivity. , 2017, Essays in biochemistry.

[9]  J. Heyda,et al.  Beyond the Hofmeister Series: Ion-Specific Effects on Proteins and Their Biological Functions. , 2017, The journal of physical chemistry. B.

[10]  Pengfei Li,et al.  Metal Ion Modeling Using Classical Mechanics , 2017, Chemical reviews.

[11]  S. Rempe,et al.  Ion-Specific Effects in Carboxylate Binding Sites. , 2016, The journal of physical chemistry. B.

[12]  D. Case,et al.  Further along the Road Less Traveled: AMBER ff15ipq, an Original Protein Force Field Built on a Self-Consistent Physical Model , 2016, Journal of chemical theory and computation.

[13]  Caitlin E. Scott,et al.  Understanding Ion Binding Affinity and Selectivity in β-Parvalbumin Using Molecular Dynamics and Mean Spherical Approximation Theory. , 2016, The journal of physical chemistry. B.

[14]  C. Stefano,et al.  Thermodynamic Study on the Protonation and Complexation of GLDA with Ca2+ and Mg2+ at Different Ionic Strengths and Ionic Media at 298.15 K , 2016 .

[15]  Q. Cui,et al.  Quantum Effects in Cation Interactions with First and Second Coordination Shell Ligands in Metalloproteins , 2015, Journal of chemical theory and computation.

[16]  C. Simmerling,et al.  ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB. , 2015, Journal of chemical theory and computation.

[17]  Martin Lepšík,et al.  Calcium Binding to Calmodulin by Molecular Dynamics with Effective Polarization. , 2014, The journal of physical chemistry letters.

[18]  John M Herbert,et al.  Aiming for benchmark accuracy with the many-body expansion. , 2014, Accounts of chemical research.

[19]  Colin P. Johnson,et al.  Quantitation of the calcium and membrane binding properties of the C2 domains of dysferlin. , 2014, Biophysical journal.

[20]  C. Lim,et al.  Competition among metal ions for protein binding sites: determinants of metal ion selectivity in proteins. , 2014, Chemical reviews.

[21]  Duncan Poole,et al.  Routine Microsecond Molecular Dynamics Simulations with AMBER on GPUs. 2. Explicit Solvent Particle Mesh Ewald. , 2013, Journal of chemical theory and computation.

[22]  Pengyu Y. Ren,et al.  The Polarizable Atomic Multipole-based AMOEBA Force Field for Proteins. , 2013, Journal of chemical theory and computation.

[23]  Pengfei Li,et al.  Rational Design of Particle Mesh Ewald Compatible Lennard-Jones Parameters for +2 Metal Cations in Explicit Solvent. , 2013, Journal of chemical theory and computation.

[24]  C. Lim,et al.  Differential role of the protein matrix on the binding of a catalytic aspartate to Mg2+ vs Ca2+: application to ribonuclease H. , 2013, Journal of the American Chemical Society.

[25]  Andreas W. Götz,et al.  SPFP: Speed without compromise - A mixed precision model for GPU accelerated molecular dynamics simulations , 2013, Comput. Phys. Commun..

[26]  P. Cremer,et al.  Role of carboxylate side chains in the cation Hofmeister series. , 2012, The journal of physical chemistry. B.

[27]  Wouter G. Touw,et al.  The second Ca(2+)-binding domain of NCX1 binds Mg2+ with high affinity. , 2011, Biochemistry.

[28]  A. Stuchebrukhov,et al.  Accounting for electronic polarization in non-polarizable force fields. , 2011, Physical chemistry chemical physics : PCCP.

[29]  Q. Cui,et al.  Electronic properties and desolvation penalties of metal ions plus protein electrostatics dictate the metal binding affinity and selectivity in the copper efflux regulator. , 2010, Journal of the American Chemical Society.

[30]  Christopher J. R. Illingworth,et al.  Computational Studies on Polarization Effects and Selectivity in K+ Channels , 2010 .

[31]  Benoît Roux,et al.  Two mechanisms of ion selectivity in protein binding sites , 2010, Proceedings of the National Academy of Sciences.

[32]  Beat Schwaller,et al.  Cytosolic Ca2+ buffers. , 2010, Cold Spring Harbor perspectives in biology.

[33]  Ingmar Persson,et al.  Hydrated metal ions in aqueous solution: How regular are their structures? , 2010 .

[34]  Ye Mei,et al.  Communications: Electron polarization critically stabilizes the Mg2+ complex in the catalytic core domain of HIV-1 integrase. , 2010, The Journal of chemical physics.

[35]  Margaret E. Johnson,et al.  Current status of the AMOEBA polarizable force field. , 2010, The journal of physical chemistry. B.

[36]  C. J. Illingworth,et al.  Many-body effects and simulations of potassium channels , 2009, Proceedings of the Royal Society A: Mathematical, Physical and Engineering Sciences.

[37]  T. Kinraide.  Improved scales for metal ion softness and toxicity , 2009, Environmental toxicology and chemistry.

[38]  C. Lim,et al.  Metal binding affinity and selectivity in metalloproteins: insights from computational studies. , 2008, Annual review of biophysics.

[39]  H. Llewelyn Roderick,et al.  Ca2+ signalling checkpoints in cancer: remodelling Ca2+ for cancer cell proliferation and survival , 2008, Nature Reviews Cancer.

[40]  M. Shimaoka,et al.  The connection between metal ion affinity and ligand affinity in integrin I domains. , 2007, Biochimica et biophysica acta.

[41]  Martin J Field,et al.  Binding of calcium and other metal ions to the EF-hand loops of calmodulin studied by quantum chemical calculations and molecular dynamics simulations. , 2007, The journal of physical chemistry. B.

[42]  H. Vogel,et al.  Structures and metal-ion-binding properties of the Ca2+-binding helix-loop-helix EF-hand motifs. , 2007, The Biochemical journal.

[43]  E. Van Cutsem,et al.  Magnesium wasting associated with epidermal-growth-factor receptor-targeting antibodies in colorectal cancer: a prospective study. , 2007, The Lancet. Oncology.

[44]  Benoit Roux,et al.  Importance of Hydration and Dynamics on the Selectivity of the KcsA and NaK Channels , 2007, The Journal of general physiology.

[45]  Pengyu Y. Ren,et al.  Towards accurate solvation dynamics of divalent cations in water using the polarizable amoeba force field: From energetics to structure. , 2006, The Journal of chemical physics.

[46]  C. Lim,et al.  A DFT/CDM Study of metal-carboxylate interactions in metalloproteins: factors governing the maximum number of metal-bound carboxylates. , 2006, Journal of the American Chemical Society.

[47]  R. MacKinnon,et al.  Principles of Selective Ion Transport in Channels and Pumps , 2005, Science.

[48]  Carmay Lim,et al.  Zn protein simulations including charge transfer and local polarization effects. , 2005, Journal of the American Chemical Society.

[49]  Wei Yang,et al.  Probing site-specific calmodulin calcium and lanthanide affinity by grafting. , 2005, Journal of the American Chemical Society.

[50]  S. Agah,et al.  Estimation of parvalbumin Ca(2+)- and Mg(2+)-binding constants by global least-squares analysis of isothermal titration calorimetry data. , 2003, Analytical biochemistry.

[51]  Carmay Lim,et al.  A combined experimental and theoretical study of divalent metal ion selectivity and function in proteins: application to E. coli ribonuclease H1. , 2003, Journal of the American Chemical Society.

[52]  David M. Gooden,et al.  Additivity and the physical basis of multivalency effects: a thermodynamic investigation of the calcium EDTA interaction. , 2003, Journal of the American Chemical Society.

[53]  Wei Yang,et al.  Rational design of a calcium-binding protein. , 2003, Journal of the American Chemical Society.

[54]  Minko Dudev,et al.  First-second shell interactions in metal binding sites in proteins: a PDB survey and DFT/CDM calculations. , 2003, Journal of the American Chemical Society.

[55]  Carmay Lim,et al.  Principles governing Mg, Ca, and Zn binding and selectivity in proteins. , 2003, Chemical reviews.

[56]  G. Phillips,et al.  Molecular mechanisms of calcium and magnesium binding to parvalbumin. , 2002, Biophysical journal.

[57]  M. Berridge,et al.  The versatility and universality of calcium signalling , 2000, Nature Reviews Molecular Cell Biology.

[58]  G. Phillips,et al.  Metal-ion affinity and specificity in EF-hand proteins: coordination geometry and domain plasticity in parvalbumin. , 1999, Structure.

[59]  S. Linse,et al.  Structural basis for the negative allostery between Ca2+‐ and Mg2+ ‐binding in the intracellular Ca2+ ‐receptor calbindin D9k , 1997, Protein science : a publication of the Protein Society.

[60]  J. Falke,et al.  Tuning the equilibrium ion affinity and selectivity of the EF-hand calcium binding motif: substitutions at the gateway position. , 1996, Biochemistry.

[61]  J. Falke,et al.  Novel ion specificity of a carboxylate cluster Mg(II) binding site: strong charge selectivity and weak size selectivity. , 1993, Biochemistry.

[62]  E. Snyder,et al.  Calcium(II) site specificity: effect of size and charge on metal ion binding to an EF-hand-like site. , 1990, Biochemistry.

[63]  T. Straatsma,et al.  THE MISSING TERM IN EFFECTIVE PAIR POTENTIALS , 1987 .

[64]  J. Hoenderop,et al.  Magnesium in man: implications for health and disease. , 2015, Physiological reviews.

[65]  Carmay Lim,et al.  Effect of carboxylate-binding mode on metal binding/selectivity and function in proteins. , 2007, Accounts of chemical research.

[66]  M. Bicho,et al.  Role of cellular magnesium in health and human disease. , 2004, Frontiers in bioscience : a journal and virtual library.