Molecular dynamics simulations of thermodynamic properties of selected polymeric and biological molecules

Abstract

Molecular dynamics (MD) simulations have been widely applied to study equilibrium and dynamical properties of macromolecular systems. In this thesis MD simulations are applied to important macromolecular processes, including conformation transformation in macromolecular systems and enzymatic catalysis, molecular details of which are inaccessible to experimental methods. A fundamental investigation of macromolecular processes is presented in this dissertation. Different computational methods, such as integrated tempering sampling (ITS), umbrella sampling (US), and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations, have been applied to study conformation changes of macromolecules including those in an enzyme catalyzed reaction. Three representative topics are investigated in this dissertation: (1) structural and dynamic relaxation behavior of polyelectrolytes confined in metal-organic framework (MOF) MIL-53(Al); (2) switch of peptide conformations between α-helix and β-hairpin states; and (3) chorismate rearrangement reaction catalyzed by ―isochorismate-pyruvate lyase from Pseudomonas aeruginosa‖ (PchB). Conformation and dynamical properties of polyelectrolytes threaded in MOF are investigated by MD simulations. A polymer threaded inside MOF was reported to have augmented conductivity and high ion-exchange kinetics. Basic understanding of confinement effect on polyelectrolytes is critical for designing novel polyelectrolyte~MOF composites. Three polyelectrolytes, sodium polyacrylate acid, sodium poly (4-vinylbenzonic acid), and polydiallyldimethylammonium chloride (PDADMA), have been introduced into MIL-53(Al) channels to elucidate the confinement effect with variation of charged groups and molecular structures. Quantitative analysis demonstrates that confinement effects include (1) increasing order and size of polyelectrolytes, (2) enabling uniform counter-ion distribution, and (3) changing dynamic relaxation and configurational entropy of polyelectrolytes in the polyelectrolyte~MIL-53(Al) composites. To efficiently sample conformation transformations of peptide, the ITS method has been used to investigate secondary structure transformation process of peptides. Proteins undergo conformational changes to fulfill their functions. Secondary structure changes between α-helix and β-hairpin, an essential feature of proteins, is explored by the ITS method. Results demonstrate that ITS can widely sample peptide conformational space, without prior knowledge of the structure or the use of a bias potential. The obtained free energy landscape is used reliably to characterize conformations changes of the peptide between α-helix and β-hairpin states. Finally, chorismate mutate reaction has been a central topic of the enzyme catalysis for decades. This reaction has attracted studies using the QM/MM scheme. However, it is still unclear whether the reaction is enthalpy driven or entropy driven. In this dissertation, the free energy changes of reaction in water are compared to corresponding enzymatic reaction catalyzed by PchB. This reaction is also studied by long timescale US simulations to illustrate the enthalpy/entropy scheme in this enzyme. Comparing the uncatalyzed reaction with the catalyzed reaction in PchB, we conclude that both enthalpy and entropy contribute to catalysis. The stable structure of bound chorismate and the enthalpy/entropy scheme are consistent with a previous hypothesis derived from experimental results.