1. 1 Key points from last lecture Many “inorganic” elements are essential for life Organisms make economic use of available resources, but also have developed mechanisms to accumulate certain elements Despite the low amount of metal ions present in living systems, they are enormously important for virtually all life processes Both deficiency and overload/excess lead to illness

2. 2 Bio-Inorganic Chemistry Lecture 2: Basic Principles and Concepts

3. 3 Overview a)Synopsis of important properties of metal ions b)Geometries and electronic structures of metal ions in Biological System c)Thermodynamics: complex stability and site selectivity Stability constants Charge Ionic radii HSAB principle Irving-Williams Series Other effects pK a values and the competition of metals with protons d)Properties important for catalysis Lewis acidity Redox potentials and electron transfer rates Ligand exchange rates e)Effect of metal environment created by protein

4. 4 General properties Characteristics Na +, K + Mg 2+, Ca 2+ Zn 2+, Ni 2+ Fe, Cu, Co, Mo, Mn Predominant oxidation state +1 +2 +2 seeTable 4 stability of complexes very low low or medium high high (except Fe 2+ and Mn 2+, medium ) preferred donor atoms O O N, S N, S (sometimes O for high oxidation states) mobility in biological systems high medium low to medium(esp. Zn) low to medium (Fe 2+ and Mn 2+ )

5. 5 Geometries Causes: see Ligand-field theory and steric factors

6. 6 +7  +6  +5  +4   +3      +2        +1   K Ca Sc Ti V Cr Mn Fe Co Ni Cu Zn Oxidation states X X X X X X X X X X X   : common in chemistry : Less common in chemistry X : Not available to biology

7. 7 Common spin states for some metal ions

8. 8 Stability aspects: Thermodynamics of metal binding Important for Understanding of: –Metal uptake and distribution –Specificity of metal binding (bio)molecules –Catalysis by metalloenzymes –Interactions of metals with nucleic acids

9. 9 Stability constants L + M  LM Often expressed as log K: e.g.: K = 10 15  log K = 15 The dissociation constant K d is K -1  log K d = -15 [M][L] [LM]  K 

10. 10 Stability constants - ranges Rough rule of thumb: Strong complexes: log K > 10 Weak complexes log K < 4

11. 11 Stability Aspects: What governs stability ? 1. charge effects Rule of thumb: The higher the charge of the cation, the more stable the complex Biophysical reason: Charge recombination is favourable But see later: HSAB principle

12. 12 2. Ionic radii Ionic radii are dependent on: –position in periodic system –charge (the higher, the smaller) –coordination number (the higher, the larger) If covalence (due to differences in electronegativity), steric hindrance etc. would not operate, z/r (charge/radius) would dictate order of stabilities In reality: seldom observed, only with very small ligands, e.g. F -

13. 13 Hard and Soft Acids and Bases HardBorderlineSoft Acids: H +, Na +, K +, Mg 2+, Ca 2+, Cr 3+, Fe 3+, Co 3+ Fe 2+, Co 2+, Ni 2+, Cu 2+, Zn 2+ Cu +, Ag +, Au +, Pt 2+, Pb 2+, Hg 2+, Cd 2+ Bases: NH 3, RNH 2, H 2 O, OH -, O 2-, ROH, RO -, RCO 2 -, PO 4 3- Ar-NH 2, ImidazoleRS -, RSR See Handout

14. 14 Hard and Soft Acids

15. 15 Stability Aspects: The Irving-Williams Series Stability order for high-spin divalent metal ion complexes Always peaks at Cu(II) Mn(II) always the minimum Underlying reasons: a) ionic radii b) LFSE Zn(II)

16. 16 Stability Aspects: Interplay between HSAB principle and the Irving- Williams Series: O,O N,N N,O S,N CuFe Figure from Sigel and McCormick, Acc. Chem. Res. 3, 201 (1970). X Y M log K High-spin M(II) complexes Bidentate ligands Trend more pronounced the softer the ligand

17. 17 Competition with protons Both metal ions and H + are positively charged and have an affinity for bases The actual concentration of a complex ML therefore depends on [M], [L], and [H + ] Low pH  high [H + ]: ML complexes dissociate  Effective (or apparent or conditional) stability constants

18. 18 Zn-Cys Zn-His Zn-Asp and Zn-Glu Calculated with: logK’ = logK + logK a – log (K a +[H + ]) and values for logK for the 1:1 Zn(aa) complexes (taken from the IUPAC stability constants database). -logK a (= pK a ): Cys: 8.5 His: 6-7 Asp/Glu: 4 logK’ 0 1 2 3 4 5 6 7 8 9 10 02468 12 Competition between protons and metal ions: Conditional stability constants of the four most common zinc ligands in proteins pH Asp (N,O) Glu (N,O) Cys (S,N) His (N,N)

19. 19 Other contributions to stability Chelate effect Preferred coordination geometry Dielectric constant of the medium: Interiors of proteins can be very different from water – usually more hydrophobic  lower dielectric constant: Enhances charge recombination and therefore complex formation

20. 20 Catalysis in Metalloenzymes

21. 21 Properties of metal ions exploited for enzymatic catalysis Lewis acidity: affinity for electrons - polarisation of substrates: - facilitation of attack by external base - increasing attacking power of bound base - pK a values of coordinated ligands are lowered E.g.: aquo-ions: pK a usually 9-10 in zinc enzymes as low as 7. Orienting the substrate and stabilising it in a conformation conducive to reaction Redox activity ++ --

22. 22 Lewis acidity: Effect on pK a of bound ligands NB: Hydrolysis of aquocomplexes From Lippard and Berg

23. 23 Importance of redox chemistry in biological systems Electron transfer reactions: Energy generation for life is based on flow of electrons - e.g. from “fuel” to O 2 (respiration) http://highered.mcgraw-hill.com/sites/0072437316/student_view0/chapter9/animations.html#

24. 24 Oxidising power increases H + /H 2 (pH 7): -0.4 V O 2 /OH - (pH 7): +0.8 V NB: Redox potentials of metal ions are highly dependent on environment and coordinated ligands Biology (ie chemistry in water) is limited to this range. Standard reduction potentials (pH 0)

25. 25 Kinetic aspects Water exchange rates Expressed as lifetime of complexes Useful to characterise reactivity in ligand exchange reactions inert labile

26. 26 Proteins tune the properties of metal ions Co-ordination number: –The lower the higher the Lewis acidity Co-ordination geometry –Proteins can dictate distortion –Distortion can change reactivity of metal ion Weak interactions in the vicinity: second shell effects –Hydrogen bonds to bound ligands –Hydrophobic residues: dielectric constant can change stability of metal-ligand bonds We’ll look at these in more detail later (lectures on zinc, copper, and iron enzymes)

27. 27 Summary The behaviour of metal ions in biological systems can be understood by combining the principles of coordination chemistry with a knowledge of the special environment created by biomolecules