Molecular Forces in Biological Systems - Electrostatic Interactions; - Shielding of charged objects in solution

Molecular Forces in Biological Systems - Electrostatic Interactions; - Shielding of charged objects in solution

Electrostatic self-energy, effects of size and dielectric constant q q r r ε ε 1 ε 2? δq ΔU = ΔW Born = δu el = qδq 4πε 0 εr brought from infinity U el = 1 4πεε 0 q2 * 1 # 1 1 & % ( = cz2 4πε 0 2r $ ε 2 ε 1 ' 2r q q 2 qdq = 8πε 0 εr 0 # 1 1 & % ( $ ε 2 ε 1 ' where c=e 2 /4πε 0 = 14.4 ev*å = 2.3*10-28 J*m For a typical small ion (r = 2 4Å) the energy of transfer between water (ε=80) and interior of cellular membrane (ε=2) is about 30 60 kcal/mol. The larger the ion, the easier is to transfer it to low dielectric medium

Biological macromolecules are stabilized by physical interactions: Strong Weak -200 - -800 kj/mol (-50 - -200 kcal/mol) Covalent bonds -40 - -400 kj/mol (-10 - -100 kcal/mol) Ionic interactions Ion-dipole interactions Hydrogen bonds Van der Waals interactions Hydrophobic effect

Why care about electrostatics? Ø Longest-range biologicaly relevant interactions. Ø A lot of biological molecules are charged. Amino acids: Asp-, Glu-, Lys+ Arg+, His+; DNA: phosphates- in backbone, lipids, salt ions, etc. Sugars Membranes trna (dense phosphate packing) dsdna

Electrostatic field V(r) = q A 4πεε 0 r q E(r) = A 4πεε 0 r 2 r r! E V ( r)! V ( r)! V ( r)! = V ( r) = i + j + k dx dy dz Energy! = q B V(r)! F ( r) = q B E Assumptions: homogeneous dielectric medium point charges no mobile ions infinite boundaries

Electrostatic force F(r) = q A q B 4πεε 0 r 2 r r Force on charge B due to charge A. Superposition U = q ref 4πε 0 ε F = q ref 4πε 0 ε i i q i x i x ref q i x i x ref 2 x i x ref x i x ref

A mean field theory replaces the interaction between elements in the system by the interaction of a single element with an effective field, which is the sum of the external field and the internal field.

Bjerrum length. The distance at which two unit charges interact with kt of energy. k l B B T = = 2 e 4πDε l 2 e 4πDε k 0 0 B B T Approximately 7 Å for water (ε = 80) at 298 o K. Electrostatic interactions are much stronger than most other nonbonded interactions; e.g., gravitational. U U U U grav elec elec grav Gm = r r e 2.30 10 = 4πε r r 2 64 p 1.87 10 2 28 c 0 1.23 10 36 J m J m

Flux of an electric field Fluxes arise from - Sources: positive charges - Sinks: negative charges Electric field flux: integral of electric displacement over a surface. Φ = Boundary surface of volume Ω Ω εe( s) d s Electric displacement Jacobian; points in surface normal direction

Gauss law The integral of field flux through a closed, simple surface is equal to the total charge inside the surface This is true for both homogeneous and inhomogeneous dielectric media Point charge in a sphere Point charge has spherically-symmetric field Field is constant on sphere surface Flux is independent of sphere diameter Φ = εe(r)4πr 2 = ε q 4πε 0 εr 2 4πr2 = q ε 0 Φ = εe( s) d s Ω = 1 ρ ( x)d x ε 0 Ω

Field from a line charge Assumptions: Homogeneous medium Line of length L, where L is very big (radial symmetry) Linear charge density of λ Φ = 2π 0 εe( s) d s (cylin der) L 0 = εe (r )r dz d θ = 2πrLεE (r ) 2πrLεE (r ) = λl ε 0 λ E (r ) = 2πεε 0 r

Field around DNA B-DNA shape: 2 phosphates every 3.4 Å water dielectric constant of 80 What is the field 40 Å away from a very long B-DNA molecule? E ( r ) = = λ 2πε 0 εr ( 1.60 10 19 C) ( 1.7 10 10 m) 2π ( 8.854 10 12 C 2 J -1 m -1 ) 80 = 5.29 10 7 V m -1 ( ) ( ) 4 10 9 m

Field from a charged plane Assumptions: Homogeneous medium Surface of area A, Surface charge density of σ Φ = 2π 0 εe( s) d s ( pillbox ) z 0 = 2 εe (r )r dz d θ = 4π R 2 εe (r ) = 2AεE (r ) 2AεE (r ) = σ A ε 0 E (r ) = σ 2εε 0 What is the field at distance r from the source?

Field around a membrane POPS membrane -1 e charge per lipid 1 lipid per 55 Å 2 What is the field 20 Å away from the membrane (in water)? Bigger than DNA!! 1 e $! σ = # & 1.60 10 19 C$! Å 2 $ # &# & " 55 Å 2 %" e %" 10 20 m % = 0.29 C m -2 E ( z ) = σ 2ε 0 ε = ( 0.29 C m -2 ) ( ) 2 2 8.854 10 12 C 2 J -1 m -1 = 8.19 10 9 V m -1 ( ) Mukhopadhyay P, et al. Biophys J 86 (3) 1601-9, 2004.

p = 3.8 Debye Electric dipole moment! p =! qr Interaction energy of a dipole with a field U p! = q r! i i i! = p! E p 1 Debye = 0.2 electron-angstroms = 3.3x10 23 Cm

Charge-Dipole and Dipole-Dipole interactions q charge - dipole + q θ a r - q U U = = static qd cosθ 2 4πε εr with Brownian tumbling q 2 2 4 ( 4πε 0ε ) 3kTr 0 d 2 static U = d1d2k 4πε εr 0 3 K orientation factor dependent on angles d 1 d 2 r with Brownian motion U 2 2 d1 d2 = 2 3kT (4πε ε ) 0 2 r 6

Partial Charges 0.37-0.57 0.64 N-Acetyl-N -Methylserinyl amide 0.25 0.46-0.54 0.27 0.74-0.53 0.64 0.06

Electrostatics of maromolecules

A continuum dielectric medium Ø Reduces the strength of electrostatic interactions relative to a vacuum. Ø It has no atomic detail. An isotropic dielectric continuum exhibits the same response in all directions q the dielectric tensor can be reduced to a scalar q for a homogeneous isotropic Coulomb s law takes a very simple, scaled form [ε(r) ϕ(r)] = ρ(r) ε 0 V(r) = ρ(r) ε 0 ε u(r) = q 1q 2 4πεε 0 r

Dielectric Boundaries Boundary can be modeled as a step function change in dielectric constant. The relevant form of the Poisson equation is: [ε(r) ϕ(r)] = ρ(r) ε 0 The dielectric discontinuity can serve as a source of E- field lines even if there are no source charges there (ρ = 0).

Image Charges & Forces When a charge approaches a dielectric discontinuity: " q image = ε ε % 2 1 $ 'Q = kq # ε 2 +ε 1 & (charge is in medium with ε 1 ) Force = kq 2 /(4πε 0 ε 1 (2d) 2 ) k < 0 when ε 1 < ε 2 (charge in low dielectric) image charge of opposite sign, force is attractive. k > 0 when ε 1 > ε 2 (charge in high dielectric) image charge of same sign, force is repulsive.

Induced dipole! p =αε 0! E A α polarizability of the molecule Interaction energy between the induced dipole and the inducing field U = E!! p de E αε!! = EdE = 0 2 0 0 1 αε E 0 2 Induced dipoles: dependent upon polarizability of molecule, how easily electrons can shuffle around to react to a charge

Induced dipoles and Van der Waals (dispersion) forces E - d = αe d dipole moment + a - polarizability d r U = αd 2 2 6 ( 4π ) ε 0εr neutral molecule in the field constant dipole induced dipole r induced dipoles (all polarizable molecules are attracted by dispersion forces) U I1I2α1α 2 = 4 ( I + I )3n r 1 I 1,2 ionization energies α 1,2 polarizabilities 2 n refractive index of the medium 6 Large planar assemblies of dipoles are capable of generating long-range interactions

van der Waals interactions this is a general term for the favorable interactions that occur between uncharged atoms van der Waals forces include: permanent dipole-permanent dipole interactions permanent dipole-induced dipole interactions dispersion interactions all have energies that depend on 1/distance 6 we consider London dispersion interactions here: these are common to all atoms even atoms that have no permanent dipoles (e.g. Ar)

London dispersion interactions also known as temporary dipole-induced dipole interactions consider an argon atom on average, its electron distribution will be spherically symmetrical: but at any instant, it will not be perfectly symmetric, e.g.: when the distribution is like this, there will be an electronic dipole: δ+ δ

London dispersion interactions now consider a second atom adjacent to the first: it will be polarized by the first atom: this will lead to a favorable dipole-dipole interaction between the two atoms the interaction occurs because the electron distributions become correlated

London dispersion interactions London J Chem Soc 33, 8-26 (1937) the magnitude of this effect depends on the distance between the two atoms: r E dispersion 1 / r 6 (negative energy à favorable) it also depends on the atoms polarizabilities (a): E dispersion a atom1 x a atom2 a describes how much an electron distribution can fluctuate or respond to an applied electric field

London dispersion interactions a (of atoms and molecules) generally increases with more electrons: relative polarizability He Ne Ar Kr Xe 0.20 0.39 1.63 2.46 4.00 boiling point 4 27 87 120 165 stronger dispersion interactions so more energy required to do this: gas phase ΔH vaporization liquid phase

London dispersion interactions the dispersion interaction between many atoms is usually approximated as a sum of London terms: E dispersion = Σ E London (r ij ) for N atoms, the total energy will be a sum of N(N-1)/2 terms this is the pairwise additivity assumption

London dispersion + sterics we can now consider the sum of the two types of interactions that we ve seen so far consider approach of two uncharged atoms (e.g. Ar) E dispersion + repulsion (kcal/mol) 3 2 1 0-1 1 term r 12 1 term r 6 total 3 3,5 4 4,5 5 5,5 6 distance between atoms(a) unfavorable electron overlap dominates at short distance favorable dispersion interaction dominates at long distance

Dispersion interactions & protein stability so favorable interactions with close-packed atoms in the folded state are partly balanced by: favorable interactions with water molecules in the unfolded state the density of atoms is higher in a protein s folded state than in water (proteins are very tightly packed) so dispersion interactions will stabilize proteins

Dispersion interactions in nature 5002000 kg 000 (theoretically) nanohairs Photo: M. Moffet Geckos get a grip using Van-der-Waalsforces Autumn et al. PNAS 99, 12252-12256 (2002)

The seta has 1 000 nanohairs The Gecko toe has 500 000 microhairs (setae) Nanostructure of the Gecko toe

Technical surface 1 Contact area Adhesion The Gecko effect through Van-der-Waals-forces Technical surface Technical surface 2 Nanohairs! Small Large contact area small large adhesion force Microhair If all of a gecko s setae were stuck to a surface at the same time it would be able to support 140 kg!

( From micro to nano contacts in biological attachment devices, Arzt et al., PNAS 100(19) 2003)) lizards spiders Small insects: Compliant pads (to shape themselves to rough surfaces) + sweat Medium insects: Multiple pads per leg + sweat Spiders and lizards: Lots of pads (hair) per foot - but dry / no secretions flies bugs beetles

Gecko-Tape Stanford University s Sticky Bot

Electrostatic Steering System Potential dependence on distance Energy [kj/mol] ion-ion r 1 250 ion-dipole r 2 15 dipol dipol r 3 2 London r 6 1 r -1 r -2 r -3 r -6 1 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0 0 2 4 6 8 10

Interaction between ions and macromolecules Non-specific screening effects Depends only on ionic strength (not species) Results of damped electrostatic potential Described by Debye-Hückel and Poisson-Boltzmann theory for low concentration Site-specific binding Ionic specific (concentration of specific ion, not necessarily ionic strength) Site geometry, electrostatics, coordination, etc. enables favorable binding Influences Co-factors Allosteric activation Folding (RNA)

Polar solvation: Poisson equation Poisson equation Classic equation for continuum electrostatics Can be derived from hard sphere dipolar solvent Assumptions No dielectric saturation (linear response) No solvent-solvent correlation (local response) ε + - + - - - + + + + - - + + - + - - + - - - - + + - + - + - + + - + + - + + - + - + - + ( ) u( ) πρ( ) u( ) u ( ) x x = 4 x for x Ω x = x for x Ω 0

Polar solvation: Boltzmann equation Mean field model Include mobile charges Boltzmann distribution Ignore charge-charge correlations Finite ion size Weak ion-ion electrostatics Low ion correlations Missing ion chemistry No detailed ion-solvent interactions No ion coordination, etc. - + - + + - - + - + - + - - + - - - + + + + - - + + - + - - + - - - - + + - + + + - + + - + + - + + - + + - + - + - + + ( x) = f ( x) + m( x) = ρ f ( x) + i i ρ ρ ρ - - - + + - + + + + + + - - - + i qce qu i - + - + - - - ( x) V( x) i

Poisson-Boltzmann equation Biomolecular The space dielectric charge distribution properies 2 4πec ε(x) u(x) z kt i δ( x x Mobile charge distribution 4πρ( x) i i ) i ε(x) ϕ(x) = 4π q i δ(x x i ) + 4πρ(x) φ( ) = 0

Mobile ion charge distribution form: Boltzmann distribution no explicit ion-ion interaction No detailed structure for atom (de)solvation Result: Nonlinear partial differential equation

For not very high ion concentrations κa << 1 V ( r) = z+ e 4πεε r 0 e κr q Viewed from beyond the counterion cloud, the macroion appears neutral. q Macroions will not feel each other until they re nearby q Once they are nearby, the detailed surface pattern of charges can be felt by its neighbor, not just overall charge - streospecificity.

Hydrogen bonds The hydrogen bonds is in the range of 3-40 kcal mol -1. The covalent bond between H and O in water is about 492 kj mol -1. The van der Waals interaction is about 5.5 kj mol -1.

A hydrogen bond consists of a hydrogen atom lying between two small, strongly electronegative atoms with lone pairs of electrons (N, O, F). Strength of an H-bond is related to the D-H---A - Distance - The D-H-A angle. The hydrogen bond is stronger than typical electrostatic interactions between partial charges, but it is easily disassociated by heat or by interaction with other atoms.

Distance Van der Waals radius of H: 1.1Å, O 1.5 Å. The closest approach should be 2.6 Å. Separation is about 1 Å less! It is 1.76 Å. Intermediate between VdW distance and typical O-H covalent bond of 0.96Å. The shorter the distance between D & A the stronger the interaction.

Hydrogen bond is directional Hydrogen bond potential energy U = A r B r A' B' cosθ + cosθ 12 6 r r 12 6 ( 1 )

The hydrogen bonds define secondary structure of proteins. They are formed between the backbone oxygens and amide hydrogens. Hydrogen bonds define protein binding specificity