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

Bio-Inorganic Chemistry

Lecture 2:

Basic Principles and Concepts

3

Overviewa) 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• pKa 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

General properties

Characteristics Na+, K+ Mg2+, Ca2+ Zn2+, Ni 2+ Fe, Cu, Co, Mo, Mn

Predominant oxidation state

+1 +2 +2 see Table 4

stability of complexes

very low low or medium

high high (except Fe2+ and Mn2+, 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 (Fe2+ and Mn2+)

5

GeometriesMetal ion Preferred geometries in small high-

spin complexes with O and N donors

Cu(II),

Mn(III)

d9

d4

tetragonal > 5-coord. > tetrahedral

Cu(I) d10 linear, trigonal planar, or tetrahedral

Co(II) d7 octahedral > tetrahedral>others

Zn(II) d10 tetrahedral > octahedral > 5-coord.

Fe(III),

Co(III),

Cr(III),

Mn(II),

Ni(II)

d5

d6

d3

d5

d8

octahedral > others

Causes: see Ligand-field theory and steric factors

6

+7 +6 +5 +4 +3 +2 +1 K Ca Sc Ti V Cr Mn Fe Co Ni Cu Zn

Oxidation states

XX X X

XXX

XXX

X

: common in chemistry: Less common in chemistryX : Not available to biology

7

Common spin states for some metal ionsTable: Common spin states for some metal ions

Metal M2+ M3+

Mn high-spin d5 high-spin d4

Fe low-spin or

high-spin d6

high-spin d5

Co high-spin d7 low-spin d6

Ni high-spin d6 low-spin d7

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

Stability constants

L + M LM

Often expressed as log K: e.g.: K = 1015 log K = 15

The dissociation constant Kd is K-1 log Kd = -15

[M][L][LM]K

10

Stability constants - ranges

Rough rule of thumb:

• Strong complexes: log K > 10

• Weak complexes log K < 4

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

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

Hard and Soft Acids and Bases

Hard Borderline Soft

Acids:H+, Na+, K+, Mg2+, Ca2+, Cr3+, Fe3+, Co3+

Fe2+, Co2+, Ni2+, Cu2+, Zn2+

Cu+, Ag+, Au+, Pt2+, Pb2+, Hg2+, Cd2+

Bases:NH3, RNH2, H2O, OH-, O2-, ROH, RO-, RCO2

-, PO43-

Ar-NH2, Imidazole RS-, RSR

• See Handout

14

Hard and Soft Acids

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 radiib) LFSE Zn(II)

16

Stability Aspects: Interplay between HSAB principle and the Irving-Williams Series:

O,O

N,N

N,O

S,N

CuFeFigure from Sigel and McCormick, Acc. Chem. Res. 3, 201 (1970).

X YM

log

K

• High-spin M(II) complexes

• Bidentate ligands

• Trend more pronounced the softer the ligand

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

Zn-Cys

Zn-His

Zn-Asp and Zn-Glu

Calculated with:

logK’ = logK + logKa – log (Ka+[H+])

and values for logK for the 1:1 Zn(aa) complexes (taken from the IUPAC stability constants database).

-logKa (= pKa): Cys: 8.5 His: 6-7 Asp/Glu: 4

logK’

0

1

2

3

4

5

6

7

8

9

10

0 2 4 6 8 10 12

Competition between protons and metal ions: Conditional stability constants of the four most common zinc

ligands in proteins

pH

Asp (N,O)Asp (N,O)

Glu (N,O)Glu (N,O)

Cys (S,N)Cys (S,N)

His (N,N)His (N,N)

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

Catalysis in Metalloenzymes

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

- pKa values of coordinated ligands are lowered

E.g.: aquo-ions: pKa usually 9-10

in zinc enzymes as low as 7.

• Orienting the substrate and stabilising it in a conformation conducive to reaction

• Redox activity

Zn2+

OR'

R

O OH- Zn2+

OR'

R

O OH

n

Zn2+

R'OH RCOOH+ + ++-

22

Lewis acidity: Effect on pKa of bound ligands

NB: Hydrolysis of aquocomplexes

From Lippard and Berg

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 O2

(respiration)

http://highered.mcgraw-hill.com/sites/0072437316/student_view0/chapter9/animations.html#

24

Oxidising powerincreases

H+/H2 (pH 7): -0.4 V

O2/OH- (pH 7): +0.8 V

Species E0 (V)

Cu2+/Cu+ +0.153

Fe3+/Fe2+ +0.771

Mn3+/Mn2+ +1.51

Co3+/Co2+ +1.842

O2 /O2– – 0.33

O2 + H+/ HO2 – 0.13

O2 + 2H+ / H2O2 +0.281

O2 + 4H+ / 2H2O +0.815

O2– + 2H+ / H2O2 +0.89

OH + H+ / H2O +2.31

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

Kinetic aspects• Water exchange rates

Expressed as lifetime of complexesUseful to characterise reactivity in ligand exchange reactions

inert labile

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

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