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With regard to the p-value, the reader should recall that this quantity changes based on the size of the dataset. Therefore this number can only be used to compare predictors tested on the same data. By this measure, FO was by far the most discriminating predictor, followed by hNMb. As explained earlier, the sensitivity, specificity, and p-value were computed under the strict criterion for statistical rigor. However, for an application most users would probably consider a prediction that came within about 5 residues of the correct hinge location to be a true positive. So we examined each of the 40 proteins and labelled each as a success, partial success, or failure on the basis of a loose criterion for each predictor c. A test was considered a success under this criterion if each prediction came within 5 residues of an annotated HAG hinge, and vice versa. It was a partial success if at least one prediction matched one HAG hinge, but one or more predictions were more than five residues from a HAG hinge, or vice versa. It was a failure if no predictions were within five residues of a HAG hinge. The evaluation for each protein under the loose criterion is presented in supplementary Table 4.5. We counted the number of successes, partial successes, and failures for the five most interesting predictors in Table 4.4. As can be seen, FO scored the most successes, followed by hNMd and hNMb. TLSMD had no successes, but this is due to the fact that as implemented on our server it reports all domain boundaries for up to 5 domains. Since the proteins in HAG have at most 3 hinges, some of the TLSMD predictions would be expected to have no corresponding HAG hinge. 190
FlexOracle (FO) The FlexOracle algorithm has the best predictive ability by several measures. It had the highest sensitivity and lowest p-value (Table 4.3). It had the most successes under the loose criterion (Table 4.4). Results for individual proteins (supplementary Table 4.5) show that FO failed for Calmodulin, Troponin C, and Elastase of Pseudomonas Aeruginosa, suggesting the method cannot deal well with proteins that depend on bound metals for stability and motion. It also fared poorly for the two proteins with 3 hinge points, as would be expected for a predictor intrinsically limited to two hinge points (supplementary Table 4.5). hNMb, hNMd hNMb and hNMd are complemented by FO, as can be seen by several cases for which FO fails but hNMb and/or hNMd succeed (Figure 4.3), as was the case for five proteins: the (open) metal-bound form of calmodulin, bacteriophage T4 lysozyme (closed), cAMP dependent protein kinase (closed), elastase of pseudomonas aeruginosa (open), and inorganic pyrophosphatase (closed). The hNMd method has a strong advantage in that unlike FO and hNMb, it is not intrinsically limited by the number of strands in the hinge. In particular, we note that FO 191
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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
Page 139 and 140: a. 139
Page 141 and 142: Figure 3.3: Folylpolyglutamate Synt
Page 143 and 144: . c. 143
Page 145 and 146: a. 145
Page 147 and 148: Figure 3.5: Lir-1 (closed) Morph ID
Page 149 and 150: . c. 149
Page 151 and 152: a. 151
Page 153 and 154: Figure 3.7: Ribose binding protein
Page 155 and 156: . c. 155
Page 157 and 158: Tables GNM 157 Single-cut predictor
Page 159 and 160: Chapter 4: HingeMaster: normal mode
Page 161 and 162: The problem of hinge prediction is
Page 163 and 164: Translation Libration Screw Motion
Page 165 and 166: ! [ K] = [ U] " [ ] 2 [ U] T Where
Page 167 and 168: generated one ROC curve for each mo
Page 169 and 170: ! ! 1 (l " k) A(k,l) = 2 % ' $ C(i,
Page 171 and 172: however, since we found that the Co
Page 173 and 174: A key part of this analysis involve
Page 175 and 176: describe its net vibrational displa
Page 177 and 178: ! Because it cuts the backbone at t
Page 179 and 180: ! ! x HingeMaster = x" # y . [6] 2
Page 181 and 182: different values of ! " * and gener
Page 183 and 184: manually select domains and color p
Page 185 and 186: E. coli resides in the periplasmic
Page 187 and 188: The results for this protein are sh
Page 189: esidues (62). As is customary we al
Page 193 and 194: extra breakpoints based on visual i
Page 195 and 196: hinge, it is usually predicted by a
Page 197 and 198: Supplementary methods Statistical t
Page 199 and 200: ! ! ! eigenvector. The resulting re
Page 201 and 202: TNC induces a conformational change
Page 203 and 204: possibility that unexpected results
Page 205 and 206: UDP-N-acetylglucosamine enolpyruvyl
Page 207 and 208: predicted both hinges, again with m
Page 209 and 210: Most predictors (including FO, Ston
Page 211 and 212: FO, hNMb, and hNMd were completely
Page 213 and 214: HingeMaster makes a strong predicti
Page 215 and 216: Figure 4.2: ROC curves for HingeMas
Page 217 and 218: Figure 4.3: HingeMaster results for
Page 219 and 220: d. e. 219
Page 221 and 222: 221
Page 223 and 224: 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
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lengths and angles)[89]. The equili
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for holo as well as apo forms, but
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queried using the “?” button. O
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coordinate. This phenomenon is know
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! At the end of each equilibration
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aborted. This marked the correspond
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sRMSD has a major limitation that m
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with respect to the starting struct
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generated structure with respect to
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Ribose Binding Protein (RBP) As des
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strikingly similar both to the holo
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energy minimization. The minimizati
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Figures Figure 5.1: Assignment of r
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Figure 5.3: Results for glutamine b
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Figure 5.4: Results for biotin carb
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Figure 5.6: Results for Adenylate K
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close to the holo. The structure wi
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Table 5.1: MolMovDB ID, PDB ID, fre
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with sRMSD; however its main utilit
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morph server, and left confident th
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9. M Gerstein RJ, T Johnson, J Tsai
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28. Wriggers W, Schulten K: Protein
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45. Dumontier M, Yao R, Feldman HJ,
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62. Thorpe MF, D.J. Jacobs, M.V. Ch
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81. Winn MD, Isupov MN, Murshudov G
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98. Morris GM, Goodsell DS, Hallida
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115. Miyazawa T: Normal Vibrations
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