Probing folding free energy landscape of small proteins through minimalistic models: folding of HP-36 and β-amyloid

Abstract

Folding dynamics and energy landscape picture of protein conformations of HP-36 and β-amyloid (Aβ) are investigated by extensive Brownian dynamics simulations, where the inter amino acid interactions are given by a minimalistic model (MM) we recently introduced [J. Chem. Phys. 118 4733 (2003)]. In this model, a protein is constructed by taking two atoms for each amino acid. One atom represents the backbone C_α atom, while the other mimics the whole side chain residue. Sizes and interactions of the side residues are all different and specific to a particular amino acid. The effect of water-mediated folding is mapped into the MM by suitable choice of interaction parameters of the side residues obtained from the amino acid hydropathy scale. A new non-local helix potential is incorporated to generate helices at the appropriate positions in a protein. Simulations have been done by equilibrating the protein at high temperature followed by a sudden quench. The subsequent folding is monitored to observe the dynamics of topological contacts (N_topo), relative contact order parameter (RCO), and the root mean square deviation (RMSD) from the realprotein native structure. The folded structures of different model proteins (HP-36 and Aβ) resemble their respective real native state rather well. The dynamics of folding shows multistage decay, with an initial hydrophobic collapse followed by a long plateau. Analysis of N_topo and RCO correlates the late stage folding with rearrangement of the side chain residues, particularly those far apart in the sequence. The long plateau also signifies large entropic free energy barrier near the native state, as predicted from theories of protein folding.