Modulation of the Intrinsic Properties of Alzheimer's Amyloid Beta Peptide with Nanosurfaces and

189 Pages·2016·9.4 MB·English

Modulation of the Intrinsic Properties of Alzheimer’s
Amyloid Beta Peptide with Nanosurfaces and
Chemical Modifications: A Computational Approach

Thesis Submitted to AcSIR for the Award of the Degree of
DOCTOR OF PHILOSOPHY
in Chemical Sciences

By

Mr. Asis Kumar Jana
Registration Number: 10CC11A26003

Under the guidance of
Dr. Neelanjana Sengupta

Physical Chemistry Division
CSIR- National Chemical Laboratory,
Pune - 411008, India

May 2016
Certificate

This is to certify that the work incorporated in this Ph.D. thesis entitled
Modulation of the Intrinsic Properties of Alzheimer’s Amyloid Beta Peptide with
Nanosurfaces and Chemical Modifications: A Computational Approach
submitted by Mr. Asis Kumar Jana to Academy of Scientific and Innovative
Research (AcSIR) in fulfillment of the requirements for the award of the
Degree of Doctor of Philosophy in Chemical Sciences, embodies original
research work under my supervision. I further certify that this work has not been
submitted to any other University or Institution in part or full for the award of
any degree or diploma. Research material obtained from other sources has
been duly acknowledged in the thesis. Any text, illustration, table etc., used in
the thesis from other sources, have been duly cited and acknowledged.

Asis Kumar Jana Dr. Neelanjana Sengupta

(Student) (Supervisor)

Date:
Place: Pune
Declaration

I hereby declare that the thesis entitled “Modulation of the Intrinsic Properties of
Alzheimer’s Amyloid Beta Peptide with Nanosurfaces and Chemical Modifications: A
Computational Approach” submitted for the degree of Doctor of Philosophy in
Chemical Sciences to the Academy of Scientific & Innovative Research (AcSIR), has
been carried out by me at the Physical and Materials Chemistry Division of CSIR-
National Chemical Laboratory, Pune under the guidance of Dr. Neelanjana Sengupta.
Such material as has been obtained by other sources has been duly acknowledged in this
thesis. The work is original and has not been submitted in part or full by me for any
other degree or diploma to any other Institution or University.

Date: Research Student
CSIR-National Chemical Laboratory, Mr. Asis Kumar Jana
Pune - 411008
Dedicated to

My Beloved Parents
and
AratiMa
Acknowledgements

During my PhD tenure at CSIR-National chemical laboratory, I have been supported,
inspired and accompanied by many people like scientists, friends, non-academic staffs
etc. It gives me great privilege to take this opportunity to express my heartfelt gratitude
for all of them.
First of all, I would like to thank my teacher and research advisor Dr.
Neelanjana Sengupta for excellent guidance, incessant encouragement and positive
criticism in every respect at all phases of research career. I consider himself extremely
fortunate to have a supervisor who not only guided me how to do research and think
independently but also taught me discipline, professionalism and shown unique ways to
reach goals. I must say, without her help it was not possible for me to complete my
research work in time. I am thankful to UGC for awarding junior and senior research
fellowship.
I owe a special debt to Dr. Mahesh J. Kulkarni and Dr. Ruchi Anand (IIT,
Bombay) and their research groups especially to Sneha Bansode, Kedar and Hussain
(IIT, Bombay) for giving me the opportunity to extend computational support in their
experimental studies and enriching scientific discussions. I would like to pay special
thanks to Dr. Bishwajit Maiti (Banaras Hindu University) for his support regarding
quantum calculations.
I owe to thank Dr. Sarika Maitra Bhattacharyya, Dr. T. G. Ajithkumar, Dr.
Kumar Vanka, Dr. Durba Sengupta and Dr. Kavita Joshi who taught me during my
course work in NCL. I also thank Dr. Srabanti Chaudhury (IISER, Pune) for appearing
my UGC upgradation seminar. I thank Prof. Ashwini Nangia, Director, NCL, Dr.
Vijaymohanan, Dr. P. A. Joy, Head, Division of Physical Chemistry and Dr. Anil Kumar
(Former HoDs, Physical Chemistry Division) for giving me the opportunity to perform
research work in NCL, Pune and providing all necessary facilities and infrastructures.
Among the non-academic staffs I am thankful to Ms. Purnima Kolhe, Ms. Deepa
Puranik, Ms. Vaishali Suryawansi and others from SAC office for their help and support
for various documentations during my PhD. I am also thankful to Parag and Rahul for
their kind help in cluster management. Special thanks to my teachers who guided me in
my school and graduation because of whom I learnt a lot.
I thank my labmates Savan, Jaya and Sneha for their help. Especially I am very
thankful to my roommate Anjani Dubey and closest friend Ashok Kumar who
encouraged and supported me in every stages of my research career. I am grateful to
Turbasu Sengupta for generously helping me to make schematic pictures and
presentations and overcoming technical problems. Sincere thanks to Deepak Kumar,
Sushma, Santhi Vardhan, Devadutta, Sabadi, Dar Manzoor, Sadhu Sir, Sharath, Tushar,
Laxmiprasad, Bishnu, Yadagiri, Krunal, Xavier, Rakesh, Brijesh, Kundan, Jugal and
Yuvraj for their constant support and help. I am also thankful to Mrityunjay Tiwari for
his help during quantum calculations.
My heartfelt thanks and appreciation to my parents for their unending support
and sacrifices they have made in raising me to this level. I would also specially thank
‘Aratima’ for her love and care that she had showered upon me since my childhood
days. I want to acknowledge my mashi ‘Kalpana’ for her love and care.
Final respects and thanks to “God Almighty” for his enormous love and
blessings.

Asis Kumar Jana
Contents
Abstract vi
Abbreviations x
List of Publications xii

1. General Introduction
1.1. Protein Folding 3
1.2. Intrinsically Disordered Proteins 5
1.2.1. The Aβ Peptide 7
1.2.2. Aβ Self-Assembly 10
1.2.3. Influence of Nanomaterials on Aβ Aggregation 12
1.3. Motivation and Outline of Thesis 13
1.4. References 14
2. Molecular Dynamics Simulations: A Brief Overview
2.1. Molecular Dynamics for Macromolecular Systems 22
2.2. Atomistic Force Fields 22
2.3. Equations of Motion 25
2.4. Thermodynamic State Control 26
2.4.1. Temperature Control 27
2.4.2. Pressure Control 28
2.5 Periodic Boundary Conditions 29
2.6 References 31

i
3. Adsorption Mechanism and Collapse Propensities of the
Full-Length, Monomeric Aβ1-42 on the Surface of a
Single-Walled Carbon Nanotube: A Molecular Dynamics
Simulation Study
3.1. Introduction 35
3.2. Materials and Methods 38
3.2.1. Setup of Peptide-SWCNT Complexes 38
3.2.2. MD Simulations and Free Energy Calculations 39
3.3. Results and Discussion 40
3.3.1. Peptide Adsorption on the SWCNT Surface 40
3.3.2. Peptide-Nanotube Interaction Energies 43
3.3.3. Propensity of Peptide Collapse 45
3.4. Conclusion 48
3.5. References 49
4. Critical Roles of Key Domains in Complete Adsorption
of Aβ Peptide on Single-Walled Carbon Nanotubes:
Insights with Point Mutations and MD Simulations.
4.1. Introduction 55
4.2. Materials and Methods 58
4.2.1. System Setups 58
4.2.2. MD Simulations 59
4.2.3. Adaptive Biasing Force Calculations 59
4.3. Results 60
4.3.1. Effect of F19I and F19Y Mutations on Peptide’s 60
Intrinsic Collapse and Adsorption on SWCNT
Surface
4.3.1.1. Effect of F19I and F19Y Mutations on 60
ii
Monomeric Compactification
4.3.1.2. Complete Adsorption on SWCNT: Role of 64
N-terminal Domains
4.3.1.3. Competition Between the Collapse and the 68
Adsorption Processes
4.3.1.4. Decoupling the Roles of Hydrophobicity and 69
-Stacking in the Adsorption Process
4.3.2. Effect of F19A Mutations on Peptide’s Intrinsic 72
Collapse and Adsorption on SWCNT Surface
4.3.2.1. Effect of F19A Mutation on Free Peptide 72
Collapse
4.3.2.2. Propensity for SWCNT Adsorption 74
4.3.2.3. Post Adsorption Peptide Collapse in NT2A 76
4.3.2.4. Enhanced Movement on Nanotube Surface 78
Arising from Weakened Tethering of HP1 in
NT2A
4.3.2.5. Dewetting Effects in Free and Surface 81
Induced Collapse
4.4. Discussion and Conclusion 83
4.5. References 85
5. Competition between Aβ Self-Association and
Adsorption on the Hydrophobic SWCNT Surface: A
Molecular Dynamics Study
5.1. Introduction 91
5.2. Methods 92
5.2.1. General Simulation Protocol 92
5.2.2. Principal Component Analysis (PCA) 93
iii
5.2.3. Aβ Monomer 93
5.2.4. Adaptive Biasing Force (ABF) Free Energy 94
Calculations
5.3. Results and Discussion 95
5.3.1. Spontaneous Small Oligomeric Assembly 95
5.3.2. SWCNT Surface Adsorption Competes with 96
Inherent Self-Assembly
5.3.3. Growth Potential of Oligomers Immobilized on the 98
Nanosurface
5.4. Summary and Conclusion 100
5.5. References 101
6. Unraveling Origins of the Heterogeneous Curvature
Dependence of Polypeptide Interactions with Carbon
Nanostructures
6.1. Introduction 108
6.2. Methods 110
6.2.1. MD Simulations 110
6.2.2. Trajectory Analyses 112
6.2.3. DFT Methods 113
6.3. Results 115
6.3.1. Surface Curvature Dependence of Protein 115
Adsorption
6.3.2. Curvature Dependence of Binding Free Energy 118
6.3.3. Insights from DFT Calculations 119
6.3.4. Interaction of Aromatic Residues with CNS 120
6.3.5. Interaction of Non-polar Aliphatic Residues with 123
CNS
iv