7.91 Amy Keating How do we use computational methods to analyze, predict, or design protein sequences and structures? Theme Methods based on physics vs, methods based on our accumulated empirical knowledge of protein properties
How do we use computational methods to analyze, predict, or design protein sequences and structures? Theme: Methods based on physics vs. methods based on our accumulated empirical knowledge of protein properties 7.91 Amy Keating
For a molecular simulation or model you need 1. a representation of the protein 2. An energy function 3. a search algorithm or optimizer
For a molecular simulation or model you need: 1. A representation of the protein 2. An energy function 3. A search algorithm or optimizer
Covalent Potential Energy Terms Covalent U,+U1 bond angle +u tU orion bond ∑ k,(b-b)2 bonds bond angle ∑k(0-20 bond angles z mproper dihedral ∑k improper dihedrals 2(- torsion ∑k1+ cos(no-6) torsions Brooks et al, J. Comput. Chem. 4: 187-217 (1983)
Covalent Potential Energy Terms UCovalent = U bond + U angle bond + Uimproper dihedral + U torsion 2 U bond = ∑ 1 kb (b − b 0 ) bonds 2 2 U angle bond = ∑ 1 kθ (θ − θ ) bond angles 2 0 Uimproper dihedral = ∑ 1 improper dihedrals 2 k Φ ( Φ − Φ 0 ) U torsion = ∑ 1 kφ[1 + cos( n φ − δ )] torsions 2 Brooks et al., J. Comput. Chem. 4: 187-217 (1983) 2
Non-Covalent Potential Energy Terms Lennard-Jones potential Non-covalent U vdw +U elec B vdw accurate approximate q91 Coulombs law i>J y
Non-Covalent Potential Energy Terms UNon -covalent = UvdW +U elec Lennard-Jones potential 12 ij ij r B 6 ij ij r C − ⎛ Bij U vdW = ∑⎜ 12 − Cij ⎞⎟ i; j ⎝ rij rij 6 ⎠ “accurate” approximate qi q j U elec = ∑ Coulomb’s law i ; j εrij
The potential energy surface is a 3N-6 dimensional space For a protein, we assume a single native-structure minimum There are many local minima, and some may be close in energy to the global minimum
The potential energy surface is a 3N-6 dimensional space. For a protein, we assume a single native-structure minimum. There are many local minima, and some may be close in energy to the global minimum. Energy X