Computational study of amyloid beta protein in implicit and explicit solvent models: Probing the initial stages of aggregation
It has been proposed that the amyloid ,3-protein (A/3-protein) plays a crucial role in the development of Alzheimer's Disease (AD). This dissertation presents the results of computational studies of the initial stages of A3-protein association. The objective of this work was to determine the stability and role of the A/3-protein monomers and low-order oligomers as metastable intermediates on the pathway for formation of larger aggregates and fibrils. A protocol based on shape complementarity is used to generate an assortment of possible dimer structures of the A310_35-protein congener. The ensemble of dimer structures are evaluated using rapidly computed estimates of the desolvation and electrostatic interaction energies to identify a putative stable dimer structure. Using the umbrella sampling method and classical molecular dynamics, the potential of mean force (PMF) associated with the dimerization of the peptide in aqueous solution is computed. The profiles of the PMF corresponding to the formation of the two putative dimer structures are compared. Molecular dynamics trajectories originating from the two putative dimer structures are used to analyze their stability. Significant attempts are made to increase the time over which the association of the A/310_35-protein can be simulated. In this respect, conformations generated by the A/310_35-protein simulated using an explicit TIP3P solvent model are compared to conformations resulting from simulations employing one empirical and two continuum electrostatics solvent models. Inspired by recent experimental results, the dynamics of the D23-K28 "salt-bridge" contacts are examined and critically evaluated as a possible "nucleation site" for the formation of ,3-structure characteristic of amyloid fibrils. The behavior of the A/321_3o-protein fragment is studied using molecular dynamics simulations employing an explicit aqueous solvent model. Special attention is paid to the VGSN(24-27) region of the protein where experimental solid-state nuclear magnetic resonance (NMR) measurements indicate that formation of a turn may play a crucial role in stabilizing the A/31_42-protein in fibril structure. The influence of two mutations, E22Q and D23N, on the thermodynamics properties of the A/321_30 fragment is analyzed and related to the possible roles played by these two naturally occurring mutations in amyloidosis.