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19. Thorpe MF, Lei M, Rader AJ, Jacobs DJ, Kuhn LA: Protein flexibility and dynamics using constraint theory. J Mol Graph Model 2001, 19(1):60-69. 20. Smith AaG, M.: in preparation 2005. 21. Porter CT, Bartlett GJ, Thornton JM: The Catalytic Site Atlas: a resource of catalytic sites and residues identified in enzymes using structural data. Nucleic Acids Res 2004, 32(Database issue):D129-133. 22. Holm L, Sander C: Removing near-neighbour redundancy from large protein sequence collections. Bioinformatics 1998, 14(5):423-429. 23. Thompson JD, Higgins DG, Gibson TJ: CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 1994, 22(22):4673-4680. 24. Schneider TD, Stormo GD, Gold L, Ehrenfeucht A: Information content of binding sites on nucleotide sequences. J Mol Biol 1986, 188(3):415-431. 25. Krebs W: The Database of Macromolecular Motions: A standardized system for analyzing and visualizing macromolecular motions in a database framework. Dissertation. New Haven: Yale University. 26. Shatsky M, Nussinov R, Wolfson HJ: Flexible protein alignment and hinge detection. Proteins 2002, 48(2):242-256. 27. Shatsky M, Fligelman ZY, Nussinov R, Wolfson HJ: Alignment of flexible protein structures. Proc Int Conf Intell Syst Mol Biol 2000, 8:329-343. 282
28. Wriggers W, Schulten K: Protein domain movements: detection of rigid domains and visualization of hinges in comparisons of atomic coordinates. Proteins 1997, 29(1):1-14. 29. Hayward S, Lee RA: Improvements in the analysis of domain motions in proteins from conformational change: DynDom version 1.50. J Mol Graph Model 2002, 21(3):181-183. 30. Flores S, Echols N, Milburn D, Hespenheide B, Keating K, Lu J, Wells S, Yu EZ, Thorpe M, Gerstein M: The Database of Macromolecular Motions: new features added at the decade mark. Nucleic Acids Res 2006, 34(Database issue):D296-301. 31. Meagher KL, Carlson HA: Incorporating protein flexibility in structure-based drug discovery: using HIV-1 protease as a test case. J Am Chem Soc 2004, 126(41):13276-13281. 32. Hespenheide BM, Rader AJ, Thorpe MF, Kuhn LA: Identifying protein folding cores from the evolution of flexible regions during unfolding. J Mol Graph Model 2002, 21(3):195-207. 33. Nagarajan N, Yona G: Automatic prediction of protein domains from sequence information using a hybrid learning system. Bioinformatics 2004, 20(9):1335-1360. 34. Marsden RL, McGuffin LJ, Jones DT: Rapid protein domain assignment from amino acid sequence using predicted secondary structure. Protein Sci 2002, 11(12):2814-2824. 35. Holm L, Sander C: Parser for protein folding units. Proteins 1994, 19(3):256- 268. 283
Page 1 and 2:
Abstract Flexibility and domain dyn
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Flexibility and domain dynamics of
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Table of Contents Table of figures
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Can hinges be predicted by a simple
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FlexOracle (FO1, FO1M, FO) 176 Defi
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Conclusions 279 References 281 Tabl
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Table of tables Table 2.1: Amino ac
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Acknowledgements Committee: Mark Ge
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Introduction The problem of predict
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Ab initio methods attempt to model
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potential for simplification, motio
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Chapter 1: The molecular motions da
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MolMovDB is a resource for studying
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voids in proteins, helix-helix pack
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A full-feature version of FIRST5 wi
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gradual transition from the initial
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energy. Thus the first residue list
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activity, DNA-directed DNA polymera
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homology table to an entry in the C
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Highlight active sites from the CSA
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Figure 1.3: Conformational change a
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particular, we found that hinges te
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and the holo. In this case it is po
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Our molecular motions database serv
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We first made a simple GOR(Garnier-
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The morph trajectory was sterically
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protein in the Jmol window to his/h
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of the hinge was otherwise unclear,
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Catalytic Sites Atlas (nonredundant
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! ! ! ! ! h c = number of times res
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! ! ! ! µ h " d c D # H . It is eq
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As mentioned earlier, the fact that
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STRIDE[50] recognizes secondary str
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! ! alignment at this position[24,
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To test this idea, we decided to ca
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GOR method is useful for predicting
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! HI active"site (i) as 0.4 for res
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lowered, and the area under the cur
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would be preferable to the other, o
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Discussion Correlations were found
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Sequence in the immediate neighborh
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Figures p-value 0.5 0.25 0 .01 PHE
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Figure 2.3: Secondary structure Res
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Figure 2.5: Conservation: full set
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Figure 2.7: Solvent accessible surf
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completely random predictor, with a
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samples 1800 1600 1400 1200 1000 80
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m = distance from nearest residues
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Hinge All Hinge Residues residues R
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in hinge residues HI p-value 1 277
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Total resid. in Hinge Atlas 54839 H
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Chi- Computer annotated set Hinge A
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BMC: Bioinformatics, we present the
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hinges. Kundu et al. use the lowest
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Domains can move relative to each o
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The quantity ! E(i) represents the
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Identification of local minima As w
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compute FoldX_energy (stability of
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energy element of each cluster was
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At least two sets of atomic coordin
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! FN (false negatives): Number of r
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We observed qualitatively (figures
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pairs of structures used to generat
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coordinate set does not significant
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The LIR family is composed of eight
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CaM is a major calcium-binding prot
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The results of running FlexOracle a
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Figure 3.2: Results for individual
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a. 139
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Figure 3.3: Folylpolyglutamate Synt
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. c. 143
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a. 145
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Figure 3.5: Lir-1 (closed) Morph ID
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. c. 149
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a. 151
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Figure 3.7: Ribose binding protein
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. c. 155
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Tables GNM 157 Single-cut predictor
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Chapter 4: HingeMaster: normal mode
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The problem of hinge prediction is
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Translation Libration Screw Motion
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! [ K] = [ U] " [ ] 2 [ U] T Where
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generated one ROC curve for each mo
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! ! 1 (l " k) A(k,l) = 2 % ' $ C(i,
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however, since we found that the Co
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A key part of this analysis involve
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describe its net vibrational displa
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! Because it cuts the backbone at t
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! ! x HingeMaster = x" # y . [6] 2
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different values of ! " * and gener
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manually select domains and color p
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E. coli resides in the periplasmic
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The results for this protein are sh
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esidues (62). As is customary we al
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FlexOracle (FO) The FlexOracle algo
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extra breakpoints based on visual i
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hinge, it is usually predicted by a
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Supplementary methods Statistical t
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! ! ! eigenvector. The resulting re
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TNC induces a conformational change
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possibility that unexpected results
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UDP-N-acetylglucosamine enolpyruvyl
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predicted both hinges, again with m
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Most predictors (including FO, Ston
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FO, hNMb, and hNMd were completely
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HingeMaster makes a strong predicti
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Figure 4.2: ROC curves for HingeMas
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Figure 4.3: HingeMaster results for
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d. e. 219
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221
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Figure 4.5: Human lactoferrin (open
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Figure 4.6: Troponin C (TNC) Morph
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Figure 4.7: Calmodulin, calcium fre
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229
Page 231 and 232: Tables Predictor Basis Max. hinge p
Page 233 and 234: test true c positive positive sensi
Page 235 and 236: 235 Closed Metal bound # of hinge p
Page 237 and 238: Chapter 5: The Conformation Explore
Page 239 and 240: ending, which involves a rigid regi
Page 241 and 242: lengths and angles)[89]. The equili
Page 243 and 244: for holo as well as apo forms, but
Page 245 and 246: queried using the “?” button. O
Page 247 and 248: coordinate. This phenomenon is know
Page 249 and 250: ! At the end of each equilibration
Page 251 and 252: aborted. This marked the correspond
Page 253 and 254: sRMSD has a major limitation that m
Page 255 and 256: with respect to the starting struct
Page 257 and 258: generated structure with respect to
Page 259 and 260: Ribose Binding Protein (RBP) As des
Page 261 and 262: strikingly similar both to the holo
Page 263 and 264: energy minimization. The minimizati
Page 265 and 266: Figures Figure 5.1: Assignment of r
Page 267 and 268: Figure 5.3: Results for glutamine b
Page 269 and 270: Figure 5.4: Results for biotin carb
Page 271 and 272: Figure 5.6: Results for Adenylate K
Page 273 and 274: close to the holo. The structure wi
Page 275 and 276: Table 5.1: MolMovDB ID, PDB ID, fre
Page 277 and 278: with sRMSD; however its main utilit
Page 279 and 280: morph server, and left confident th
Page 281: 9. M Gerstein RJ, T Johnson, J Tsai
Page 285 and 286: 45. Dumontier M, Yao R, Feldman HJ,
Page 287 and 288: 62. Thorpe MF, D.J. Jacobs, M.V. Ch
Page 289 and 290: 81. Winn MD, Isupov MN, Murshudov G
Page 291 and 292: 98. Morris GM, Goodsell DS, Hallida
Page 293 and 294: 115. Miyazawa T: Normal Vibrations
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