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研究生:羅杰
研究生(外文):Mahalingam Rajasekaran
論文名稱:Structural and Dynamic Characterization of Common Polymorphisms in N-Acetyltransferase 2 (NAT2) and Homeodomain of Pituitary Homeobox Protein 2 (PITX2)
指導教授:陳金榜
指導教授(外文):Chen, Chinpan
學位類別:博士
校院名稱:國立清華大學
系所名稱:生物資訊與結構生物研究所
學門:生命科學學門
學類:生物訊息學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
論文頁數:313
中文關鍵詞:乙型乙醯轉移酵素分子動力學模擬乙型腦下垂體同源箱蛋白同源區域Gromacs單核苷酸基因多態性蛋白質動力學
外文關鍵詞:NAT2Molecular dynamics simulationPITX2 homeodomainGromacsSNPProtein dynamics
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Single nucleotide polymorphisms (SNPs) are the most common source of human genetic variation, occurring at a frequency of 1 in every 1000 nucleotide bases of the 3 billion bases human genome. SNPs can be intronic or exonic and can thus affect mRNA transcription, structure, splicing and translation, protein expression, structure, enzymatic activity and stability. SNPs are linked large number of genetic defects and also associated with many diseases. In this study we analyzed structural and dynamical effects of some of the important SNPs from Arylamine N-acetyltransferase 2 (NAT2) and the transcription factor pituitary homeobox protein 2 (PITX2).
NAT2 is an important catalytic enzyme that metabolizes the carcinogenic arylamines, hydrazine drugs and chemicals. This enzyme is highly polymorphic in different human populations. Several polymorphisms of NAT2, including the single amino acid substitutions R64Q, I114T, D122N, L137F, Q145P, R197Q, and G286E, are classified as slow acetylators, whereas the wild-type NAT2 is classified as a fast acetylator. The slow acetylators are often associated with drug toxicity and efficacy as well as cancer susceptibility. The biological functions of these 7 mutations have previously been characterized, but the structural basis behind the reduced catalytic activity and reduced protein level is not clear. We performed multiple molecular dynamics simulations of these mutants as well as NAT2 to investigate the structural and dynamical effects throughout the protein structure, specifically the catalytic triad, cofactor binding site, and the substrate binding pocket. None of these mutations induced unfolding; instead, their effects were confined to the inter-domain, domain 3 and 17-residue insert region, where the flexibility was significantly reduced relative to the wild-type. Structural effects of these mutations propagate through space and cause a change in catalytic triad conformation, cofactor binding site, substrate binding pocket size/shape and electrostatic potential. Our results showed that the dynamical properties of all the mutant structures, especially in inter-domain, domain 3 and 17-residue insert region were affected in the same manner. Similarly, the electrostatic potential of all the mutants were altered and also the functionally important regions such as catalytic triad, cofactor binding site, and substrate binding pocket adopted different orientation and/or conformation relative to the wild-type that may affect the functions of the mutants. Overall, our study may provide the structural basis for reduced catalytic activity and protein level, as was experimentally observed for these polymorphisms.
PITX2 is involved in genetic control of development. Mutations in PITX2, most in the homeodomain, cause the autosomal-dominant disorder Rieger syndrome. The mutants L16Q, K50E and R53P destabilize the structure and disrupt DNA-binding activity. The biological functions of these mutants have been characterized but not the structural basis behind the loss of DNA-binding activity. We performed multiple molecular dynamics simulations at 37º C to investigate the structural and dynamic effects of these mutants. Compared with the wild type (WT), the L16Q mutant induces a kink in the alpha 3 helix, which is stabilized by the hydrogen bond of Q21-R59. The disruption in backbone hydrogen bonds of V47-N51 and W48-R52 leads to a kink formation in the α3 helix of K50E. The R53P mutant alters the relative orientation of helices, which is apparently stabilized by the formation of new hydrogen bonds of T38-Q11, T38-Q12, T38-R2, N39-R2, L40-Q1, L40-R2, and T41-Q4. The hydrophobic core residues F8, L13, L40 and V45 change their positions in all mutants to break the hydrophobic core. Thus, changes in helical orientations and hydrophobic core cause rearrangement of the DNA-binding surface and disrupt DNA-binding activity in the mutants. The structural and molecular dynamics properties of 3 PITX2 homeodomain mutants differ from those of the WT, especially in formation of a kink in the recognition helix, change in the packing of helices and disruption of the hydrophobic core. Overall, our study may provide the structural basis for reduced catalytic activity and protein level, as was experimentally observed for these polymorphisms in NAT2 and the structural basis for the loss of DNA-binding activity for these polymorphisms in PITX2 homeodomain.

Abstract i
List of Tables iv
List of Figures v
Abbreviations vii

CHAPTER 1

1.1 Prologue 2
1.2 Scope of the thesis 5
1.3 Outline of the thesis 9

CHAPTER 2

2.1 MD simulation theory 13
2.1.1 The Born-Oppenheimer approximation 14
2.1.2 Classical description of nuclear dynamics 16
2.1.3 Force field 16
2.2 Simulation details 19
2.2.1 Integration method and time step 19
2.2.2 Solvent environment 20
2.2.3 System boundaries 20
2.2.4 Temperature and pressure coupling 22
2.2.5 Improving efficiency 23
2.2.6 Efficient calculation of non-bonded forces 23
2.2.7 Parallel computing 24

CHAPTER 3

3.1 Introduction 26
3.2 Materials and Methods 30
3.2.1 Starting structure 30
3.2.2 Molecular dynamics simulation 30
3.2.3 Analysis of molecular dynamics trajectories 31
3.3 Results and discussion 32
3.3.1 Effects of the mutations on NAT2 global structure 32
3.3.2 Effects of the mutations on NAT2 structural flexibility 32
3.3.3 Hydrogen bond changes at the mutational site 33
3.3.4 Effects of the mutations on NAT2 local tertiary structure 34
3.3.5 Effects of the mutations on NAT2 catalytic triad conformation 35
3.3.6 Effects of the mutations on NAT2 cofactor and substrate binding pocket 35
3.3.7 Effects of the mutations on NAT2 electrostatic potential 37

CHAPTER 4

4.1 Introduction 56
4.2 Materials and Methods 57
4.2.1 Starting structure 57
4.2.2 MD simulation 58
4.2.3 Analysis of MD trajectories 59
4.3 Results 59
4.3.1 Effects of the mutations on PITX2 homeodomain global structure................59
4.3.2 Mutational effects on the flexibility 60
4.3.3 Hydrophobic core changes on the mutants 60
4.3.4 Changes of helical properties on the mutants 61
4.3.5 Changes of electrostatics and DNA-binding surfaces on the mutants 63
4.4 Discussion 64

CHAPTER 5

5.1 Epilogue 81
5.2 What remains to be done? 83
5.2.1 NAT2 simulation with Acetyl CoA. 83
5.2.2 Simulation of other NAT2 mutants 84
5.2.3 Simulation of other PITX2 homeodomain mutants with DNA 84
5.2.4 Simulation of other homolog homeodomains 84
References 86

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