Digital Biology L. Ridgway Scott University of Chicago Ariel Fern´andez Rice University Release 0.4 DO NOT DISTRIBUTE October 3, 2014 Draft: October 3, 2014, do not distribute Contents 1 How is biology digital? 1 1.1 Exercises....................................... ... 4 2 Digital rules for proteins 5 2.1 Digitalnatureofmolecules. ........ 5 2.1.1 Digitalnatureofatoms. .... 5 2.1.2 Ionicrules.................................... 9 2.1.3 Carbon/hydrogenrules. .... 9 2.2 Digitalnatureofproteins. ........ 10 2.2.1 Hydrophobicityandhydrophilicity . ....... 11 2.2.2 Solvation =salvation............................... 11 6 2.2.3 Energeticambivalence . .... 12 2.3 Pchemomics...................................... .. 13 2.3.1 Anewtool?.................................... 14 2.3.2 Dataminingdefinition . ... 15 2.3.3 Datamininglens ................................ 15 2.3.4 Hydrogen bonds are orientation-dependent . ......... 16 2.3.5 Whatisananswer?............................... 16 2.4 Multiscalemodels................................ ..... 17 2.5 Hydrophobicinteractions. ....... 19 2.5.1 Solventmediationofelectricforces . ......... 20 2.5.2 Dehydrons..................................... 22 2.5.3 Dynamicsofdehydrons. ... 22 2.5.4 Simulateddynamics ............................. .. 25 2.5.5 Stickinessofdehydrons. ..... 26 2.6 Dehydronswitch .................................. ... 26 2.7 Exercises....................................... ... 27 3 Electrostatic forces 29 3.1 Directbonds..................................... ... 29 3.1.1 Covalentbonds ................................. 29 3.1.2 Ionicbonds/saltbridges . ..... 30 i CONTENTS CONTENTS 3.1.3 Hydrogenbonds.................................. 31 3.1.4 Cation-π interactions............................... 32 3.2 Charge-forcerelationship . ......... 32 3.3 Interactionsinvolvingdipoles . .......... 33 3.3.1 Single-file dipole-dipole interactions . ............ 34 3.3.2 Parallel dipole-dipole interactions . ........... 36 3.3.3 Dipolestability ............................... ... 37 3.3.4 Differentdipoles............................... ... 39 3.4 vanderWaalsforces ............................... .... 39 3.4.1 Lennard-Jonespotentials. ...... 40 3.5 Induceddipoles .................................. .... 41 3.5.1 Debyeforces................................... 41 3.5.2 Londondispersionforces . ..... 42 3.5.3 Dipole-neutralinteractions . ........ 43 3.6 Exercises....................................... ... 44 4 Protein basics 45 4.1 Chainsofaminoacidresidues . ....... 45 4.1.1 Taxonomiesofaminoacids. .... 46 4.1.2 Wrappingofhydrogenbonds. .... 49 4.2 Specialbonds .................................... ... 51 4.2.1 SaltBridges................................... 51 4.2.2 Disulfidebonds ................................. 51 4.3 Post-translationalmodifications . ........... 53 4.4 Specialsidechains ............................... ..... 53 4.4.1 Glycine(andAlanine) ............................ .. 54 4.4.2 Proline....................................... 54 4.4.3 Arginine...................................... 54 4.4.4 Lysine ....................................... 55 4.4.5 Cysteine...................................... 55 4.4.6 Aromaticsidechains ............................. .. 55 4.4.7 Rememberingcodenames . .. 56 4.5 Sidechainionization. ....... 56 4.6 Saltions........................................ .. 58 4.7 Aminoacidfrequencies............................. ..... 58 4.7.1 Choiceofdatabase .............................. .. 59 4.7.2 PDBdetails.................................... 60 4.7.3 Hetatoms ..................................... 61 4.8 Exercises....................................... ... 61 Draft: October 3, 2014, do not distribute ii CONTENTS CONTENTS 5 Protein Structure 65 5.1 Hydrogenbondsandsecondarystructure . ......... 65 5.1.1 Secondarystructureunits . ..... 66 5.1.2 Folds/domains ................................. 68 5.2 Mechanicalpropertiesofproteins . .......... 69 5.2.1 Conformationalgeometryofproteins . ........ 69 5.2.2 Dihedralangles ................................ .. 71 5.2.3 φ,ψ versus ψ,φ: the role of θ .......................... 73 5.2.4 Sidechainrotamers ............................. ... 73 5.3 Pairfrequenciesinproteins. ......... 74 5.3.1 Pairfrequencydefinitions . ..... 74 5.3.2 Applicationtoproteinsequences . ...... 76 5.3.3 Like-chargedpairs ............................. ... 76 5.4 Volumeofproteinconstituents. ......... 77 5.5 Foldnetworks .................................... ... 80 5.6 Exercises....................................... ... 82 6 Hydrogen bonds 85 6.1 Typesofhydrogenbonds. ..... 86 6.1.1 Hydrogenbondsinproteins . ... 87 6.1.2 Hydrogenbondstrength . .. 87 6.2 Identificationofhydrogenpositions . ........... 90 6.2.1 Fixedhydrogenpositions. ..... 91 6.2.2 Variablehydrogenpositions . ...... 91 6.2.3 Ambiguoushydrogenpositions. ..... 91 6.3 Geometriccriteriaforhydrogenbonds . .......... 93 6.4 Specialclassesofhydrogenbonds . ......... 94 6.4.1 Saltbridgehydrogenbonds . .... 94 6.4.2 Carboxyl-carboxylate hydrogen bonds. ......... 94 6.4.3 Aromatichydrogenbonds . .. 95 6.4.4 Carbonaceoushydrogenbonds. ..... 95 6.5 Exercises....................................... ... 95 7 Determinants of protein-protein interfaces 97 7.1 Directbonds..................................... ... 97 7.2 Hydrophobicinteractions. ....... 98 7.3 Amino acids at protein-protein interfaces . ............ 100 7.4 Interfacepropensity. ....... 103 7.5 Aminoacidpairsatinterfaces . ....... 106 7.5.1 Pairinteractionsatinterfaces . ........ 106 7.5.2 Coreversusrim................................. 108 7.5.3 Furtherstudies ................................ 110 Draft: October 3, 2014, do not distribute iii CONTENTS CONTENTS 7.6 Hotspots ......................................... 111 7.7 Conclusionsaboutinterfaces . ......... 111 7.8 Exercises....................................... 112 8 Wrapping electrostatic bonds 115 8.1 Roleofnonpolargroups ............................ ..... 115 8.1.1 Unitofhydrophobicity . 117 8.1.2 Defininghydrophobicity . .... 117 8.2 Assessingpolarity................................ ..... 119 8.2.1 Electronegativityscale . ...... 119 8.2.2 Polarityofgroups.............................. 120 8.3 Countingresidues................................ ..... 122 8.3.1 Desolvationdomain. 123 8.3.2 Predictingaggregation . ..... 125 8.4 Countingnonpolargroups . ...... 126 8.4.1 Distribution of wrapping for an antibody complex . ........... 127 8.4.2 Residuesversuspolargroups. ...... 128 8.5 Defining dehydrons via geometric requirements . ............. 129 8.6 Dynamicmodels ................................... 132 8.7 Geneticcode..................................... 133 8.7.1 Interpretationofthegeneticcode . ........ 135 8.7.2 Sizematters................................... 137 8.8 Exercises....................................... 138 9 Stickiness of dehydrons 141 9.1 Surfaceadherenceforce. ....... 141 9.1.1 Biologicalsurfaces . .... 141 9.1.2 Solubleproteinsonasurface. ...... 142 9.2 Atwo-zonemodel.................................. 142 9.2.1 Boundaryzonemodel. 143 9.2.2 Diffusionzonemodel ............................. 143 9.2.3 Modelvalidity................................. 144 9.3 Directforcemeasurement . ...... 144 9.4 Membranemorphology .............................. .... 146 9.4.1 Proteinadsorption ............................. 146 9.4.2 Densityofinvaginations . ..... 147 9.5 Kineticmodelofmorphology. ....... 147 9.6 Exercises....................................... 148 10 Electrostatic force details 151 10.1 Globalaccumulationofelectricforce . ............ 151 10.2 Dipole-dipoleinteractions . .......... 153 10.2.1 Dipole-dipoleconfigurations . ........ 154 Draft: October 3, 2014, do not distribute iv CONTENTS CONTENTS 10.2.2 Two-parameter interaction configuration . ........... 156 10.2.3 Threedimensionalinteractions. ......... 159 10.2.4 Applicationtotwo-angleproblem . ....... 161 10.3 Chargedinteractions . ....... 161 10.3.1 Charge-dipoleinteractions . ........ 162 10.3.2 Charge-chargeinteractions . ........ 163 10.4 Generalformofachargegroup . ....... 165 10.4.1 Asymptoticsofgeneralpotentials . ........ 166 10.4.2 Applicationof(10.54) . .... 167 10.5 Quadrupolepotential . ....... 168 10.5.1 Opposingdipoles .............................. 168 10.5.2 Four-cornerquadrupole. ...... 169 10.5.3 Quadrupoleexample . 170 10.5.4 Water: dipoleorquadrupole? . ...... 171 10.6 Multipolesummary............................... ..... 173 10.7 Madelungconstants. ...... 173 10.8Furtherresults ................................. ..... 175 10.8.1 Dipoleinductionbydipoles . ...... 175 10.8.2 Modifieddipoleinteraction. ....... 176 10.8.3 HydrogenplacementforSerandThr . ..... 177 10.9Exercises...................................... .... 178 11 Case studies 181 11.1Basiccases..................................... .... 181 11.1.1 Asingularcase: signaling . ...... 181 11.1.2 Formingstructures . .... 182 11.1.3 Crystalcontacts. .... 183 11.2 Enzymaticactivity . .. .. .. .. .. ... .. .. .. .. .. ... .. ...... 184 11.3 Neurophysin/vasopressinbinding . .......... 185 11.3.1 Theroleoftyrosine-99 . ..... 185 11.3.2 Theroleofphenylalanine-98 . ....... 187 11.3.3 2BN2versus1JK4 ................................ 188 11.4 Variations in proteomic interactivity . ............. 188 11.4.1 Interactivitycorrelation . ........ 190 11.4.2 Structuralinteractivity . ........ 192 11.5 Sheetsofdehydrons. ...... 195 11.6Exercises...................................... .... 195 12 Aromatic interactions 197 12.1 Partialchargemodel . ...... 198 12.2 Cation-π interactions..................................