Forces • inter-atomic interactions – electrostatic - Coulomb's law, dielectric constant – hydrogen-bonds – charge-dipole, dipole-dipole, dipole-quadrapole – polarizability – van der Waals, London dispersion (stickiness) – cation-pi (Arg/Lys to aromatic) – aromatic ring-stacking (Phe, Tyr, Trp, His) • hydrophobic effect – driving force • enthalpy balanced against entropy – G=H-TS – H adds contributions from 100s of interactions at ~1kcal/mol each – yet net stability of proteins is often G ~ 15 kcal/mol
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Forces
• inter-atomic interactions– electrostatic - Coulomb's law, dielectric constant– hydrogen-bonds– charge-dipole, dipole-dipole, dipole-quadrapole– polarizability– van der Waals, London dispersion (stickiness)– cation-pi (Arg/Lys to aromatic)– aromatic ring-stacking (Phe, Tyr, Trp, His)
• hydrophobic effect – driving force• enthalpy balanced against entropy
– G=H-TS– H adds contributions from 100s of interactions at ~1kcal/mol
each– yet net stability of proteins is often G ~ 15 kcal/mol
Warshel, Russell, and Churg (1984) -• without solvation effects, lone ionized groups would be highly unfavorable to bury in non-polar environments, and salt bridges would predominate folding with G=~-30kcal/mol• with “self-energy”, G=~1-4kcal/mol
pKa estimation (protonation state)• ionizable residues: Arg, Lys, Asp, Glu, His, Nterm, Cterm• Cys, Tyr can also get deprotonated• H++: solve Poisson-Boltzmann equation
– protonation state depends on energy of charge presence in local electrostatic potential field
• parameters for H-bond energy term in crystallographic refinement (Michael Chapman)
• Cys often acts as a donor in H-bonds– Cys, Met rarely participate in H-bonds as acceptor– more often involved in VDW interactions (hydrophobic)
• “Hydrogen bonds involving sulfur atoms in proteins”, Gregoret..(2004).– Met as acceptor, <25%– free Cys: donor ~72%, acceptor ~36%
• Non-hydrogen bond interactions involving the methionine sulfur atom. Pal D, Chakrabarti P. (1998)– Out of a total of 1276 Met residues,
• 22% exhibit S O interaction (with an average distance 3.6A), ⋅⋅⋅• 8% interact with an aromatic face (S-aromatic-atom dist. being 3.6A) • 9% are in contact with an aromatic atom at the edge (3.7A).
Can the lone-pair on sulfur in Met and Cys act as an H-bond acceptor?
interactions
• Misura, Morozov, Baker (2004)• anisotropy of side-chain interactions• geometry: preference for planar (face-on) interactions• strength?
– FireDock uses:
E=-1.5..-0.5 kcal/mol
for contact dist 5.5-7.5Å
Cation- interactions• Gallivan and Dougherty (1999)• 3.6-3.8Å, face-on vs. edge-on • frequency: ~1 per 77 residues (1/2 as common as salt bridges)