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Introduction 239 Method 243 Determining and recording the hinge location 243 Assignment of domains and calculation of centers of mass 244 Preparation of protein and ligand 246 Definition of Rotations 247 Optional equilibration 248 Angle calculation 249 Re-docking 249 Computing the radius of gyration, stability, and domain distortion 250 Holo, redocked, predicted, starting, apo, and aborted structures 251 Exploration of angular orientation space 252 Display of results 253 sRMSD benchmarking 253 Training the fitness function on Glutamine binding protein (GlnBP) 254 Results 255 Biotin Carboxylase 255 Adenylate Kinase (ADK) 260 MurA 261 Discussion 262 Prediction of protein conformational change 262 Potential applications and future work 262 Conclusions 263 10
Conclusions 279 References 281 Table of figures Figure 1.1: The new morph page. 38 Figure 1.2: The motion of an ethane molecule as determined by geometric simulation in FRODA. 39 Figure 1.3: Conformational change and functional grouping. 40 Figure 2.1: Residue type 85 Figure 2.2: Distance from active sites 86 Figure 2.3: Secondary structure 87 Figure 2.4: Physicochemical properties 88 Figure 2.5: Conservation: full set 89 Figure 2.6: Conservation: enzymes dataset 90 Figure 2.7: Solvent accessible surface area 91 Figure 2.8: ROC curve for HingeSeq 92 Figure 2.9: Amino acid composition of MolMovDB vs. PDB 93 Figure 2.10: Overlap between manual and computer annotated datasets 94 Figure 2.11: Resampling of glycine occurrence in hinge vs. non-hinge residues 95 Figure 3.1: Fragmenting the protein 136 Figure 3.2: Results for individual proteins 137 Figure 3.3: Folylpolyglutamate Synthetase (closed) 139 Figure 3.4: AMPA Receptor GluR2 (closed) 142 11
Page 1 and 2: Abstract Flexibility and domain dyn
Page 3 and 4: Flexibility and domain dynamics of
Page 5 and 6: Table of Contents Table of figures
Page 7 and 8: Can hinges be predicted by a simple
Page 9: FlexOracle (FO1, FO1M, FO) 176 Defi
Page 13 and 14: Table of tables Table 2.1: Amino ac
Page 15 and 16: Acknowledgements Committee: Mark Ge
Page 17 and 18: Introduction The problem of predict
Page 19 and 20: Ab initio methods attempt to model
Page 21 and 22: potential for simplification, motio
Page 23 and 24: Chapter 1: The molecular motions da
Page 25 and 26: MolMovDB is a resource for studying
Page 27 and 28: voids in proteins, helix-helix pack
Page 29 and 30: A full-feature version of FIRST5 wi
Page 31 and 32: gradual transition from the initial
Page 33 and 34: energy. Thus the first residue list
Page 35 and 36: activity, DNA-directed DNA polymera
Page 37 and 38: homology table to an entry in the C
Page 39 and 40: Highlight active sites from the CSA
Page 43 and 44: Figure 1.3: Conformational change a
Page 45 and 46: particular, we found that hinges te
Page 47 and 48: and the holo. In this case it is po
Page 49 and 50: Our molecular motions database serv
Page 51 and 52: We first made a simple GOR(Garnier-
Page 53 and 54: The morph trajectory was sterically
Page 55 and 56: protein in the Jmol window to his/h
Page 57 and 58: of the hinge was otherwise unclear,
Page 59 and 60: Catalytic Sites Atlas (nonredundant
Page 61 and 62:
! ! ! ! ! h c = number of times res
Page 63 and 64:
! ! ! ! µ h " d c D # H . It is eq
Page 65 and 66:
As mentioned earlier, the fact that
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STRIDE[50] recognizes secondary str
Page 69 and 70:
! ! 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
Page 85 and 86:
Figures p-value 0.5 0.25 0 .01 PHE
Page 87 and 88:
Figure 2.3: Secondary structure Res
Page 89 and 90:
Figure 2.5: Conservation: full set
Page 91 and 92:
Figure 2.7: Solvent accessible surf
Page 93 and 94:
completely random predictor, with a
Page 95 and 96:
samples 1800 1600 1400 1200 1000 80
Page 97 and 98:
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
Page 107 and 108:
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
Page 113 and 114:
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
Page 135 and 136:
The results of running FlexOracle a
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Figure 3.2: Results for individual
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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
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Chapter 4: HingeMaster: normal mode
Page 161 and 162:
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
Page 185 and 186:
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
Page 195 and 196:
hinge, it is usually predicted by a
Page 197 and 198:
Supplementary methods Statistical t
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! ! ! 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
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
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Figure 4.2: ROC curves for HingeMas
Page 217 and 218:
Figure 4.3: HingeMaster results for
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d. e. 219
Page 221 and 222:
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
Page 237 and 238:
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
Page 289 and 290:
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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