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Figure 3.8: Calmodulin (open, calcium bound form) Morph ID: f958972-2168 PDB ID: 3cln HAG hinges: 80,81 b. The TINKER version of the single-cut predictor gives ambiguous results for this calcium-bound protein, but good results for the calcium-free form (molmovdb.org/FO). The FoldX single-cut predictor, worked well for both calcium-bound and calcium-free forms Calmodulin. Nonetheless we recommend caution when treating metal-bound proteins, since the two-cut predictor had mixed results here. c. The 2-cut predictor results: Primary prediction: residues 30-33,66-69 Additional predictions: 104-107;84-87 Although the primary prediction does not coincide with the annotated hinge, upon inspecting the corresponding morph (78252-5656) we observed that indeed there are hinges coinciding with the predicted location, although they result in less backbone motion than the hinge at residue 80. Similar points (residues ~36,63) are annotated hinges in the evolutionarily related Troponin C (morph 333010-30921). In the interest of maintaining the objectivity of the HAG, we did not update the hinge annotation. We further note that the third lowest-energy local minimum (84-87) is close to the HAG hinge. Thus although the first prediction did not coincide with the HAG, the results nonetheless yield significant insight into the flexibility of the protein. 156
Tables GNM 157 Single-cut predictor (TINKER) Single-cut predictor (FoldX) Two-cut predictor 1 Total residues in HAG 13246 13246 13246 13246 2 Test positives 1279 923 292 268 3 Gold Standard positives 152 152 152 152 4 True positives TP (2 ∩ 3) 39 24 14 62 5 False Positives FP (2 - 4) 1240 899 278 206 6 False Negatives FN (3 - 4) 113 128 138 90 7 True Negatives TN (1-2-6) 11854 12195 12816 12888 8 Sensitivity (TP/(TP+FN)) 0.26 .157 .092 .41 9 Specificity (TN/(TN+FP)) .9053 .93 .98 .98 10 p-value 8.4⋅10 -9 1.3⋅10 -4 6.7⋅10 -6 3.5⋅10 -66 Table 3.1: Summary of predictor results. “Test positives” for GNM were those residues with first normal mode displacement below 0.02. Recall that the displacements are normalized to range from 0 to 1. For the single-cut predictors, test positives were residues identified as defining a local minimum per the algorithm described in the text. Lastly, “test positives” for the two-cut predictor are those selected under the strict criterion (4-residue window) also described in the text.
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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
Page 105 and 106: Chi- Computer annotated set Hinge A
Page 107 and 108: BMC: Bioinformatics, we present the
Page 109 and 110: hinges. Kundu et al. use the lowest
Page 111 and 112: Domains can move relative to each o
Page 113 and 114: The quantity ! E(i) represents the
Page 115 and 116: Identification of local minima As w
Page 117 and 118: compute FoldX_energy (stability of
Page 119 and 120: energy element of each cluster was
Page 121 and 122: At least two sets of atomic coordin
Page 123 and 124: ! FN (false negatives): Number of r
Page 125 and 126: We observed qualitatively (figures
Page 127 and 128: pairs of structures used to generat
Page 129 and 130: 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: . c. 155
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 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
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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
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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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