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the associated PDB-deposited structure files. We also chose two of the forty proteins to discuss in detail here (figures 4,5 and below), and six more in the supplementary information. We also present results for two specific proteins in this article, with several more in the supplementary information. For Glutamine binding protein, FO, hNMb, and hNMd were completely successful. hNMd, however, predicted a rather wide range of residues for the second hinge location. StoneHinge did not predict the second largest domain as a single domain, instead predicting it as multiple smaller domains. Web tools Hinge prediction server Most of the predictors discussed here can be run by the public on single-chain proteins by making a submission through the hinge prediction server linked from the front page of our server, molmovdb.org. When the job is complete, the user receives an email with a link to the generated morph page. The “Hinge Analysis Tools” box has links to output from the five predictors. The most useful of these is the “Combined predictor page,” which shows the results of all analyses in a single graph, as was done for this article. Also, buttons are available to highlight the hinges predicted by HingeMaster, TLSMD, and StoneHinge in the jmol window. Lastly, it is possible to color the protein by HingeMaster flexibility, as we will describe below. It is also possible for the user to 182
manually select domains and color proteins on this basis for didactic purposes, by first selecting the hinge sites using the Hinge Annotation tool and then using our Render Studio. Hinge Annotation Tool To manually annotate the hinges in a submitted protein, one can use the Hinge Annotation Tool in the hinge analysis toolbox, on the morph page. This tool consists of three rows of arrow buttons which allow for the selection of up to three hinge locations. A “?” button on each row returns the residue number of the current selected hinge location. A “Show all” button highlights all selected hinge locations. A “Reset highlighting” button returns to the default view. The “Submit” button must be clicked for these annotations to be entered into our database. There will appear a “display public hinge” button which will allow all users to view the selected residues in the jmol window. With minor modification, this tool was used to annotate the HAG hinge locations used in this work. Render Studio As discussed above, high resolution “domain style” images similar to those in the figures can be generated by the public by following these steps: 183
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
Page 131 and 132: The LIR family is composed of eight
Page 133 and 134: CaM is a major calcium-binding prot
Page 135 and 136: The results of running FlexOracle a
Page 137 and 138: 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: different values of ! " * and gener
Page 185 and 186: E. coli resides in the periplasmic
Page 187 and 188: The results for this protein are sh
Page 189 and 190: esidues (62). As is customary we al
Page 191 and 192: FlexOracle (FO) The FlexOracle algo
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
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test true c positive positive sensi
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235 Closed Metal bound # of hinge p
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Chapter 5: The Conformation Explore
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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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