Dr. R. Sankar, BSE 631 (2018)

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3 Pauling, Corey and Branson

4 Diffraction of DNA

5 In short, stereochemistry is important in determining which helices are possible, and integral symmetry has no role whatever

6 The α-helix and the γ-helix

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8 α-helix Secondary Structure

9 α-helix 3.6 residues per turn Translation per residue 1.5 Å Translation 5.4 Å per turn C=O (i) H-N (i+4) φ = -57 ; ψ = -47 (classical value) φ = -62 ; ψ = -41 (crystal structures) Preference of residues in helix Can proline occur in a helix? Average helix length ~ 10 residues Amphipathic helix Helical Wheel projection

10 Helical Wheel representation

11 α-helix has a net dipole

12 Right-handed α-helix or Left-handed α-helix?

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17 Antiparallel β-sheet

18 Antiparallel β-sheet

19 Parallel β-sheet

20 β-strand Polypeptide fully extended 2.0 residues per turn Translation 3.4Å per residue Stable when incorporated into a β-sheet H-bonds between peptide groups of adjacent strands Adjacent strands can be parallel or antiparallel

21 Parameters for regular secondary structures φ ψ Antiparallel β-sheet Parallel β-sheet Right-handed α-helix helix π-helix Polyproline I Polyproline II Polyglycine II

22 Turns Secondary structures are connected by loop regions Lengths vary; shapes irregular Loop regions are at the surface of the molecule Rich in charged and polar hydrophilic residues Role: connecting units; binding sites; enzyme active sites Loops are often flexible; adopt different conformations β-turns: Type I, Type II etc. γ-turns; classical, inverse G.D. Rose et al., Adv. Protein Chemistry 37 (1985) 1-109

23 Thrombin

24 Turns

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26 Thrombin Heavy chain: IVEGSDAEIGMSPWQVMLFRKSPQELLCGASLISDRWVLTAAHCLLYPPWDKNFTENDLLVRIGKHSRTRYERNIEKISMLEKIYIHPRYNWRENLDRDIAL MKLKKPVAFSDYIHVCLPDRETAASLLQAGYKGRVTGWGNLKETWTANVGKGQPSVLQVVNLPIVERPVCKDSTRIRITDNMFCAGYKPDEGKRGDACE GDSGGPFVMKSPFNNRWYQMGIVSWGEGCDRDGKYGFY THVFRLKKWIQKVIDQFGE Light Chain: TFGSGEADCGLRPLFEKKSLEDKTERELLESYIDGR

27 Growth of Protein Data Bank 26,880 structures (24/08/2003) 32,355 structures (25/08/2005) 38,198 structures (15/08/2006) 45,055 structures (7/08/2007) 52,402 structures (12/08/2008) 59,330 structures (7/08/2009) 67,131 structures (10/08/2010) 75,246 structures (16/08/2011) 83,983 structures (21/08/2012) 93,252 structures (20/08/2013) 102,550 structures (12/08/2014) 121,821 structures (17/08/2016) 132,905 structures (23/08/2017) 143,392 structures (16/08/2018)

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29 HEADER HYDROLASE(SERINE PROTEINASE) 24-OCT-91 1PPB 1PPB 2 COMPND ALPHA-THROMBIN (E.C ) COMPLEX WITH 1PPB 3 COMPND 2 D-PHE-PRO-ARG CHLOROMETHYLKETONE (PPACK) WITH 1PPB 4 COMPND 3 CHLOROMETHYLKETONE REPLACED BY A METHYLENE GROUP 1PPB 5 SOURCE HUMAN (HOMO SAPIENS) PLASMA 1PPB 6 AUTHOR W.BODE 1PPB 7 REVDAT 1 31-JAN-94 1PPB 0 1PPB 8 JRNL AUTH W.BODE,I.MAYR,U.BAUMANN,R.HUBER,S.R.STONE, 1PPB 9 JRNL AUTH 2 J.HOFSTEENGE 1PPB 10 JRNL TITL THE REFINED 1.9 ANGSTROMS CRYSTAL STRUCTURE OF 1PPB 11 JRNL TITL 2 HUMAN ALPHA-THROMBIN: INTERACTION WITH 1PPB 12 JRNL TITL 3 D-PHE-PRO-ARG CHLOROMETHYLKETONE AND SIGNIFICANCE 1PPB 13 JRNL TITL 4 OF THE TYR-PRO-PRO-TRP INSERTION SEGMENT 1PPB 14 JRNL REF /EMBO$ J. V PPB 15 JRNL REFN ASTM EMJODG UK ISSN PPB 16 REMARK 1 1PPB 17 REMARK 1 REFERENCE 1 1PPB 18 REMARK 1 AUTH W.BODE,D.TURK,A.KARSHIKOV 1PPB 19 REMARK 1 TITL THE REFINED 1.9-ANGSTROMS CRYSTAL STRUCTURE OF 1PPB 20 REMARK 1 TITL 2 D-PHE-PRO-ARG CHLOROMETHYLKETONE-INHIBITED HUMAN 1PPB 21 REMARK 1 TITL 3 ALPHA-THROMBIN. STRUCTURE ANALYSIS, OVERALL 1PPB 22 REMARK 1 TITL 4 STRUCTURE, ELECTROSTATIC PROPERTIES, DETAILED 1PPB 23 REMARK 1 TITL 5 ACTIVE-SITE GEOMETRY, AND STRUCTURE-FUNCTION 1PPB 24 REMARK 1 TITL 6 PROPERTIES 1PPB 25 REMARK 1 REF PROTEIN SCI. V PPB 26 REMARK 1 REFN US ISSN PPB 27 REMARK 1 REFERENCE 2 1PPB 28 REMARK 1 AUTH A.KARSHIKOV,W.BODE,A.TULINSKY,S.R.STONE 1PPB 29 REMARK 1 TITL ELECTROSTATIC INTERACTIONS IN THE ASSOCIATION OF 1PPB 30 REMARK 1 TITL 2 PROTEINS: AN ANALYSIS OF THE THROMBIN-HIRUDIN 1PPB 31 REMARK 1 TITL 3 COMPLEX 1PPB 32 REMARK 1 REF PROTEIN SCI. V PPB 33 REMARK 1 REFN US ISSN PPB 34

30 SEQRES 1 L 36 THR PHE GLY SER GLY GLU ALA ASP CYS GLY LEU ARG PRO 1PPB 136 SEQRES 2 L 36 LEU PHE GLU LYS LYS SER LEU GLU ASP LYS THR GLU ARG 1PPB 137 SEQRES 3 L 36 GLU LEU LEU GLU SER TYR ILE ASP GLY ARG 1PPB 138 SEQRES 1 H 259 ILE VAL GLU GLY SER ASP ALA GLU ILE GLY MET SER PRO 1PPB 139 SEQRES 2 H 259 TRP GLN VAL MET LEU PHE ARG LYS SER PRO GLN GLU LEU 1PPB 140 SEQRES 3 H 259 LEU CYS GLY ALA SER LEU ILE SER ASP ARG TRP VAL LEU 1PPB 141 SEQRES 4 H 259 THR ALA ALA HIS CYS LEU LEU TYR PRO PRO TRP ASP LYS 1PPB 142 SEQRES 5 H 259 ASN PHE THR GLU ASN ASP LEU LEU VAL ARG ILE GLY LYS 1PPB 143 SEQRES 6 H 259 HIS SER ARG THR ARG TYR GLU ARG ASN ILE GLU LYS ILE 1PPB 144 SEQRES 7 H 259 SER MET LEU GLU LYS ILE TYR ILE HIS PRO ARG TYR ASN 1PPB 145 SEQRES 8 H 259 TRP ARG GLU ASN LEU ASP ARG ASP ILE ALA LEU MET LYS 1PPB 146 SEQRES 9 H 259 LEU LYS LYS PRO VAL ALA PHE SER ASP TYR ILE HIS PRO 1PPB 147 SEQRES 10 H 259 VAL CYS LEU PRO ASP ARG GLU THR ALA ALA SER LEU LEU 1PPB 148 SEQRES 11 H 259 GLN ALA GLY TYR LYS GLY ARG VAL THR GLY TRP GLY ASN 1PPB 149 SEQRES 12 H 259 LEU LYS GLU THR TRP THR ALA ASN VAL GLY LYS GLY GLN 1PPB 150 SEQRES 13 H 259 PRO SER VAL LEU GLN VAL VAL ASN LEU PRO ILE VAL GLU 1PPB 151 SEQRES 14 H 259 ARG PRO VAL CYS LYS ASP SER THR ARG ILE ARG ILE THR 1PPB 152 SEQRES 15 H 259 ASP ASN MET PHE CYS ALA GLY TYR LYS PRO ASP GLU GLY 1PPB 153 SEQRES 16 H 259 LYS ARG GLY ASP ALA CYS GLU GLY ASP SER GLY GLY PRO 1PPB 154 SEQRES 17 H 259 PHE VAL MET LYS SER PRO PHE ASN ASN ARG TRP TYR GLN 1PPB 155 SEQRES 18 H 259 MET GLY ILE VAL SER TRP GLY GLU GLY CYS ASP ARG ASP 1PPB 156 SEQRES 19 H 259 GLY LYS TYR GLY PHE TYR THR HIS VAL PHE ARG LEU LYS 1PPB 157 SEQRES 20 H 259 LYS TRP ILE GLN LYS VAL ILE ASP GLN PHE GLY GLU 1PPB 158 SEQRES 1 I 4 PHE PRO ARG CH2 1PPB 159 FTNOTE 1 1PPB 160

31 FTNOTE 1 1PPB 160 FTNOTE 1 THR L 1H - PHE L 1G OMEGA ANGLE = PPB 161 FTNOTE 1 PEPTIDE BOND DEVIATES SIGNIFICANTLY FROM TRANS CONFORMATION 1PPB 162 FTNOTE 2 1PPB 163 FTNOTE 2 TYR L 14J - ILE L 14K OMEGA ANGLE = PPB 164 FTNOTE 2 PEPTIDE BOND DEVIATES SIGNIFICANTLY FROM TRANS CONFORMATION 1PPB 165 FTNOTE 3 1PPB 166 FTNOTE 3 ILE L 14K - ASP L 14L OMEGA ANGLE = PPB 167 FTNOTE 3 PEPTIDE BOND DEVIATES SIGNIFICANTLY FROM TRANS CONFORMATION 1PPB 168 FTNOTE 4 1PPB 169 FTNOTE 4 GLY L 14M - ARG L 15 OMEGA ANGLE = PPB 170 FTNOTE 4 PEPTIDE BOND DEVIATES SIGNIFICANTLY FROM TRANS CONFORMATION 1PPB 171 FTNOTE 5 1PPB 172 FTNOTE 5 CIS PROLINE - PRO H 37A 1PPB 173 FTNOTE 6 1PPB 174 FTNOTE 6 SER H 129B - LEU H 129C OMEGA ANGLE = PPB 175 FTNOTE 6 PEPTIDE BOND DEVIATES SIGNIFICANTLY FROM TRANS CONFORMATION 1PPB 176 FTNOTE 7 1PPB 177 FTNOTE 7 PHE H 204A - ASN H 204B OMEGA ANGLE = PPB 178 FTNOTE 7 PEPTIDE BOND DEVIATES SIGNIFICANTLY FROM TRANS CONFORMATION 1PPB 179 FTNOTE 8 1PPB 180 FTNOTE 8 GLU H GLY H 219 OMEGA ANGLE = PPB 181 FTNOTE 8 PEPTIDE BOND DEVIATES SIGNIFICANTLY FROM TRANS CONFORMATION 1PPB 182

32 HELIX 1 1 GLU L 14C SER L 14I 1 3.6/13 1PPB 188 HELIX 2 2 ALA H 56 LEU H PPB 189 HELIX 3 3 PRO H 60B PRO H 60C 5 TURN 1PPB 190 HELIX 4 4 ARG H 126 SER H 129B 1 3.6/13 1PPB 191 HELIX 5 5 ARG H 165 LYS H /13 CONTINUING HELIX/ID6 1PPB 192 HELIX 6 6 LYS H 169 SER H CONTINUING HELIX/ID5 1PPB 193 HELIX 7 7 VAL H 231 TRP H CONTINUING HELIX/ID8 & ID9 1PPB 194 HELIX 8 8 ILE H 238 ILE H /13 CONT.HELIX/ID7 & ID9 1PPB 195 HELIX 9 9 VAL H 241 GLN H CONTINUING HELIX/ID7 & ID8 1PPB 196 SHEET 1 B1 7 PRO H 28 SER H 36A 0 1PPB 197 SHEET 2 B1 7 PRO H 37 ASP H PPB 198 SHEET 3 B1 7 ARG H 50 THR H PPB 199 SHEET 4 B1 7 LEU H 99 LYS H PPB 200 SHEET 5 B1 7 LYS H 81 ASN H PPB 201 SHEET 6 B1 7 VAL H 66 ILE H PPB 202 SHEET 7 B1 7 PRO H 28 SER H 36A-1 1PPB 203 SHEET 1 B2 7 GLY H 133 LEU H PPB 204 SHEET 2 B2 7 GLY H 150 ILE H PPB 205 SHEET 3 B2 7 ASN H 179 GLY H PPB 206 SHEET 4 B2 7 GLY H 226 HIS H PPB 207 SHEET 5 B2 7 ARG H 206 VAL H PPB 208 SHEET 6 B2 7 GLY H 196 SER H PPB 209 SHEET 7 B2 7 GLY H 133 LEU H PPB 210 SSBOND 1 CYS L 1 CYS H 122 1PPB 211 SSBOND 2 CYS H 42 CYS H 58 1PPB 212 SSBOND 3 CYS H 168 CYS H 182 1PPB 213 SSBOND 4 CYS H 191 CYS H 220 1PPB 214

33 ATOM 289 N ILE H PPB 510 ATOM 290 CA ILE H PPB 511 ATOM 291 C ILE H PPB 512 ATOM 292 O ILE H PPB 513 ATOM 293 CB ILE H PPB 514 ATOM 294 CG1 ILE H PPB 515 ATOM 295 CG2 ILE H PPB 516 ATOM 296 CD1 ILE H PPB 517 ATOM 297 N VAL H PPB 518 ATOM 298 CA VAL H PPB 519 ATOM 299 C VAL H PPB 520 ATOM 300 O VAL H PPB 521 ATOM 301 CB VAL H PPB 522 ATOM 302 CG1 VAL H PPB 523 ATOM 303 CG2 VAL H PPB 524 ATOM 304 N GLU H PPB 525 ATOM 305 CA GLU H PPB 526 ATOM 306 C GLU H PPB 527 ATOM 307 O GLU H PPB 528 ATOM 308 CB GLU H PPB 529 ATOM 309 CG GLU H PPB 530 ATOM 310 CD GLU H PPB 531 ATOM 311 OE1 GLU H PPB 532 ATOM 312 OE2 GLU H PPB 533 ATOM 313 N GLY H PPB 534 ATOM 314 CA GLY H PPB 535 ATOM 315 C GLY H PPB 536 ATOM 316 O GLY H PPB 537 ATOM 317 N SER H PPB 538 ATOM 318 CA SER H PPB 539 ATOM 319 C SER H PPB 540 ATOM 320 O SER H PPB 541 ATOM 321 CB SER H PPB 542 ATOM 322 OG SER H PPB 543

34 HETATM 2414 O HOH PPB2635 HETATM 2415 O HOH PPB2636 HETATM 2416 O HOH PPB2637 HETATM 2417 O HOH PPB2638 HETATM 2418 O HOH PPB2639 HETATM 2419 O HOH PPB2640 HETATM 2420 O HOH PPB2641 HETATM 2421 O HOH PPB2642 HETATM 2422 O HOH PPB2643 HETATM 2423 O HOH PPB2644 HETATM 2424 O HOH PPB2645 HETATM 2425 O HOH PPB2646 HETATM 2426 O HOH PPB2647

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