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Free energy calculation of biomolecules using molecular dynamics simulation

  • 이주호 (대학원 생명정보공학과 생명정보공학전공)

초록/요약

Molecular dynamics (MD) is a simulation method widely used to study the physical movements of particles. The particles are allowed to interact for a given time, which result in a dynamical evolution of the system. By means of statistical mechanics, the free energy, which is one of the most important general concepts in physical chemistry, can be expressed in terms of averages over ensembles generated by MD simulation. Using this technique, free energy calculation for ligand binding to biomolecules has been well-established. In this thesis, I present my computational studies applying binding free energy calculation, which include 1) molecular mechanics – Poisson-Boltzmann surface area (MM-PBSA) method and 2) potential of mean force (PMF) using steered molecular dynamics (SMD). 1) Human beta-defensin-3 (hBD3) is an endogenous antimicrobial peptide exhibiting a broad spectrum of antibacterial activity without cytotoxic activity against eukaryotic cells. In this work, we carried out molecular dynamics (MD) simulation to explore the principle mechanism for the antibacterial activity of hBD3s to both gram-negative (GN) and gram-positive (GP) bacterial membrane in terms of structure and thermodynamics. The hBD3 binds to the GP membrane deeply as comparing with its adsorption on the GN membrane due to its strong electrostatic interaction with the GP membrane induced by the enriched POPG lipids. On the surface of both bacterial membranes, the hBD3 orientation was stabilized when the electric dipole moment was pointing toward the membrane. We next analyzed the binding free energy decompositions for the hBD3-membrane complex using MM-PBSA method. The results show that in both the GN and GP membrane systems, all types of interactions are provided effectively as for Arg17, which is a possibly key residue to control the antibacterial activity of hBD3. On the other hands, there is a dramatic difference in the energy contribution of Lys26 between the membrane systems, suggesting that it is the key factor to regulate the selectivity of the hBD3. Our finding will shed light on a principle of antibacterial activity of hBD3 on the bacterial membranes and insight for the design of potent antimicrobial peptides targeting multidrug resistance bacteria. 2) Neurotoxic plaques composed of 39 to 42 residue-long amyloid beta peptides (Aβs) are copiously present in the brains of patients with Alzheimer’s disease (AD). Erythrosine B (ER), a xanthene food dye, inhibits the formation of Aβ fibrils and Aβ-associated cytotoxicity in vitro. Here, in an attempt to elucidate the inhibition mechanism, we performed molecular dynamics (MD) simulations to demonstrate the conformational change of Aβ40 induced by ER molecules in atomistic detail. During the simulation, the ER bound to the surfaces of both N-terminus and C-terminus regions of Aβ40. Our result shows that ER interacts with the aromatic side chains at the N-terminus region resulting in destabilization of the inter-chain stacking of Aβ40. Moreover, the stability of the helical structures at the residues from 13 to 16 suggests that ER disturbs conformational transition of Aβ40. At the C-terminus region, the bound ER blocks water molecules and stabilizes the α-helical structure. Regardless of the number of ER molecules used, the interruption of the formation of the salt-bridge between aspartic acid 23 and lysine 28 occurred. To further validate our analysis, binding free energies of ER at each binding sites were evaluated. The finding of stronger binding energy at the N-terminus region supports an inhibition mechanism induced by stacking interaction between ER and phenylalanine. These findings could aid present and future treatment studies for AD by clarifying the inhibition mechanism of ER on the conformational transition of Aβ40 at the molecular level.

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Contents

Abstract ..................................................................................................................... I
List of Tables .......................................................................................................... IV
List of Figures ........................................................................................................ VI
Chapter 1. Introduction
1.1 Molecular dynamics simulation ........................................................................ 1
1.1.1.Equation of Motion .................................................................................... 1
1.1.2. Force fields ................................................................................................ 2
1.2 Free energy calculation ..................................................................................... 3
1.2.1. MM-PBSA ................................................................................................. 4
1.2.2. Potential of Mean Force using SMD ......................................................... 5
1.3. Reference .......................................................................................................... 8
Chapter 2. Molecular insights into the adsorption mechanism of human β-defensin-3 on bacterial membranes
2.1 Introduction ..................................................................................................... 10
2.2 Methods............................................................................................................ 13
2.2.1 System construction .................................................................................. 13
2.2.2 Molecular dynamics simulation ................................................................ 17
2.2.2 MM-PBSA ................................................................................................ 20
2.2.3 Orientation angle ....................................................................................... 21
2.3 Results and Discussion .................................................................................... 22
2.3.1 Selectivity for bacterial membrane ........................................................... 23
2.3.2 Adsorption orientation of hBD3 on the bacterial membrane .................... 27
2.3.3 Disruption of bacterial membrane induced by hBD3 monomer ............... 31
2.3.4 Binding free energy analysis of the hBD3- membrane complex .............. 34
2.4. Conclusion and Summary .............................................................................. 41
2.5. Reference ........................................................................................................ 43
Chapter 3. Investigation of the effect of erythrosine B on amyloid beta peptide by using molecular modeling
3.1 Introduction ..................................................................................................... 49
3.2 Methods............................................................................................................ 51
3.2.1 Parameterization of ER ............................................................................. 51
3.2.2 Molecular dynamics simulation ................................................................ 51
3.2.3 Steered molecular dynamics simulation ................................................... 55
3.2.4 Simulation analyses .................................................................................. 59
3.3 Results and Discussion .................................................................................... 60
3.3.1 Binding of ER on the Aβ40 peptide surface ............................................. 63
3.3.2 Stabilization of α-helical structure in ER treatment condition .................. 68
3.3.3 Disturbance of the formation of the salt-bridge by binding of ERs .......... 72
3.3.4 Binding free energy analysis of the Aβ40 – ER complex ......................... 74
3.3.5 Further sampling with a different Aβ40 monomer state ........................... 78
3.4. Conclusion and Summary .............................................................................. 80
3.5. Reference ........................................................................................................ 81

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