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Supplementary figures Supplementary Figure 5.8: Various predictive measures vs. sRMSD, for Glutamine Binding Protein. A: Gyration radius decreases smoothly with sRMSD, and thus improves convergence as discussed in the text, as well as excluding from consideration structures which are more, rather than less extended than the starting structure. It is not by itself a good fitness function because it is trivially possible to minimize it by interpenetrating the domains. B: Docked energy also decreases with sRMSD, but is also not a good predictor because some structures can be generated which minimize this quantity but which have the binding cleft in the wrong location. C: Domain distortion appears to be anti-correlated 276
with sRMSD; however its main utility is in excluding unphysical structures from consideration which might have been selected by the preceding two measures. D: Free energy of folding (or stability) similarly is not a good predictor but is effective in detecting and excluding unphysical conformations which might minimize docked energy or gyration radius. Supplementary Figure 5.9: The fitness function vs. sRMSD, for Glutamine Binding Protein. Combining the four predictive measures into a single function results in relatively smooth convergence and reliable discrimination of correct vs. incorrect structures. 277
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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
Page 225 and 226: Figure 4.6: Troponin C (TNC) Morph
Page 227 and 228: Figure 4.7: Calmodulin, calcium fre
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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: Table 5.1: MolMovDB ID, PDB ID, fre
Page 279 and 280: morph server, and left confident th
Page 281 and 282: 9. M Gerstein RJ, T Johnson, J Tsai
Page 283 and 284: 28. Wriggers W, Schulten K: Protein
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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