Dynamical stability and assembly cooperativity of ß-sheet amyloid oligomers--effect of polarization.

The soluble intermediate oligomers of amyloidogenic proteins are suspected to be more cytotoxic than the mature fibrils in neurodegenerative disorders. Here, the dynamic stability and assembly cooperativity of a model oligomer of human islet amyloid polypeptide (hIAPP) segments were explored by means of all-atom molecular dynamics (MD) simulations under different force fields including AMBER99SB, OPLS, and polarized protein-specific charge (PPC) model. Simulation results show that the dynamic stability of ß-sheet oligomers is seriously impacted by electrostatic polarization. Without inclusion of polarization (simulation under standard AMBER and OPLS force field), the ß-sheet oligomers are dynamically unstable during MD simulation. For comparison, simulation results under PPC give significantly more stable dynamical structures of the oligomers. Furthermore, calculation of electrostatic interaction energy between the neighboring ß strands with an approximate polarizable method produces energetic evidence for cooperative assembly of ß-strand oligomers. This result supports a picture of downhill-like cooperative assembly of ß strands during fibrillation process. The present study demonstrates the critical role of polarization in dynamic stability and assembly cooperativity of ß-sheet-rich amyloid oligomers.

An efficient approach for ab initio energy calculation of biopolymers.

We present a new method for efficient total-energy calculation of biopolymers using the density-matrix (DM) scheme based on the molecular fractionation with conjugate caps (MFCC) approach. In this MFCC-DM method, a biopolymer such as a protein is partitioned into properly capped fragments whose density matrices are calculated by conventional ab initio methods which are then assembled to construct the full system density matrix. The assembled full density matrix is then employed to calculate the total energy and dipole moment of the protein using Hartree-Fock or density-functional theory methods. Using this MFCC-DM method, the self-consistent-field procedure for solving the full Hamiltonian problem is avoided and an efficient approach for ab initio energy calculation of biopolymers is achieved. Two implementations of the approach are presented in this paper. Systematic numerical studies are carried out on a series of extended polyglycines CH3CO-(GLY)n-NHCH3(n = 3-25) and excellent results are obtained.