Molecular modelling and simulation of retroviral proteins and nanobiocomposites

Table of Contents

General introduction

Motivation for present research

1 Structural and docking analysis of HIV-1 integrase and Transportin-SR2 interaction: Is this a more general and specific route for retroviral nuclear import and its regulation?

1.1 Overview

1.2 The problem to solve

1.3 Computational methods

1.3.1 Structural analysis software

1.3.2 Sequence analysis software

1.3.3 Docking programs

1.4 Results and discussion

1.4.1 Highly similar sequences of TR-SR2 and TR-SR1 have different 3D folding domain structures

1.4.2 Where does HIV-1 integrase bind to TR-SR2?

1.4.3 Hydrogen bonds involved in the binding between HIV-1 IN NLS and the H8-loop of TR-SR2 Ran-GDP binding domain

1.4.4 Role of highly accessible and hydrophilic amino acids in HIV-1 IN and TR-SR2 interaction

1.4.5 Is this a general type of viral transport interaction?

1.5 Conclusions

2 Role of the central polypurine tract in retroviral nuclear import (analysis of the HIV-1 central polypurine tract in a foamy virus vector background)

2.1 Overview

2.2 A molecular biology challenge

2.3 Materials and methods

2.3.1 Materials and solutions

2.3.2 General molecular genetics methods

2.3.3 General cell biology methods

2.4 Results and discussion

2.5 Conclusions

3 Lead expansion and virtual screening of Indinavir derivate HIV-1 protease inhibitors using pharmacophoric - shape similarity scoring function

3.1 Overview

3.2 The strategy

3.3 Computational methods

3.3.1 HIV-1 subtype C protease and Indinavir structures

3.3.2 Protease active site detection

3.3.3 Compound library generation

3.3.4 ADME/Tox Studies

3.3.5 Protein-ligand docking

3.3.6 Construction of pharmacophore models

3.4 Results and discussion

3.5 Conclusions

4 Molecular dynamics simulation of POPC and POPE lipid membrane bilayers enforced by an intercalated single-wall carbon nanotube

4.1 Overview

4.2 The simulation and its goals

4.3 Computational methods

4.4 Results and discussion

4.5 Conclusions

Concluding discussion

Summary

Zusammenfassung

Research Objectives and Themes

The core objective of this doctoral thesis is to utilize advanced computational methods—specifically molecular modelling, molecular docking, and molecular dynamics—to elucidate the structural and functional properties of complex biological systems. The research primarily addresses the internuclear transport mechanisms of retroviruses, the virtual screening of novel HIV-1 protease inhibitors to combat drug resistance, and the stabilization of lipid membrane bilayers through the integration of single-wall carbon nanotubes.

• Mechanistic investigation of HIV-1 integrase interactions with host nuclear pore complex proteins.
• Comparative analysis of retroviral nuclear import, specifically focusing on foamy viruses versus lentiviruses.
• In silico drug design and lead expansion for novel, resistant-variant-effective HIV-1 protease inhibitors.
• Atomistic molecular dynamics simulation of lipid-nanotube hybrid systems to assess membrane stabilization dynamics.

Excerpt from the Book

Chapter Summaries

1 Structural and docking analysis of HIV-1 integrase and Transportin-SR2 interaction: Is this a more general and specific route for retroviral nuclear import and its regulation?: This chapter investigates the role of Transportin-SR2 in the nuclear import of HIV-1 integrase through 3D alignment and protein-protein docking simulations.

2 Role of the central polypurine tract in retroviral nuclear import (analysis of the HIV-1 central polypurine tract in a foamy virus vector background): This section analyzes whether replacing the foamy virus central polypurine tract with that of HIV-1 improves the transduction efficiency of foamy viral vectors in non-dividing cells.

3 Lead expansion and virtual screening of Indinavir derivate HIV-1 protease inhibitors using pharmacophoric - shape similarity scoring function: This chapter details the computational design and screening of 1300 novel compounds to identify new HIV-1 protease inhibitors capable of overcoming viral resistance.

4 Molecular dynamics simulation of POPC and POPE lipid membrane bilayers enforced by an intercalated single-wall carbon nanotube: This chapter presents a molecular dynamics simulation study examining the structural stabilization of lipid bilayers by single-wall carbon nanotubes under varying temperature conditions.

Key Keywords

Molecular modelling, Molecular dynamics, Molecular docking, HIV-1 integrase, Transportin-SR2, Retroviral nuclear import, Foamy virus, Preintegration complex, Indinavir, HIV-1 protease, Virtual screening, Pharmacophore, Lipid membrane bilayer, Carbon nanotube, Nanobiocomposites

Frequently Asked Questions

What is the primary focus of this dissertation?

This thesis focuses on applying computational techniques, specifically molecular dynamics, homology modelling, and docking, to study complex biological interactions relevant to virology and materials science.

What are the main research areas covered?

The study covers the mechanisms of HIV-1 nuclear import, the development of novel HIV protease inhibitors, and the structural stabilization effects of carbon nanotubes on lipid membrane bilayers.

What is the ultimate goal of the docking simulations performed in this work?

The primary goals are to understand the specific protein-protein interactions facilitating viral nuclear import and to design new lead compounds that can effectively inhibit viral enzymes that have evolved resistance.

Which computational methods are employed?

Key methods include homology modelling, rigid and flexible protein-protein/receptor-ligand docking (using AutoDock and PatchDock), molecular dynamics simulations (using GROMACS and VMD), and pharmacophore-based virtual screening.

What does the main body of the research address?

The main body examines the specific transport pathways of HIV-1, tests the hypothesis that central polypurine tracts are crucial for preintegration complex formation in different retroviruses, and analyzes the stability of lipid/nanotube hybrids.

Which specific keywords characterize this research?

The research is characterized by terms such as molecular modelling, HIV-1 integrase, foamy virus vectors, molecular docking, and carbon nanotube-stabilized lipid bilayers.

How does this thesis evaluate the interaction between HIV-1 integrase and Transportin-SR2?

The thesis identifies critical hydrogen bond formations and domain-specific binding sites by performing flexible docking simulations between the HIV-1 integrase NLS and the H8-loop of Transportin-SR2.

What were the findings regarding the potential for new HIV-1 protease inhibitors?

Computational screening identified a unique hit compound that, compared to Indinavir, showed potential for distinct binding modes and sustained efficacy against resistant viral strains by forming stronger hydrogen bonds with the protease active site.

Why are carbon nanotubes being studied in the context of lipid bilayers?

Carbon nanotubes are explored for their unique property to restrain the conformational freedom of lipids, which contributes to the stabilization of membrane bilayers, particularly under high-temperature conditions.