Many common human diseases are associated with the solubility equilibrium of organic matter, including the amyloid plaques seen in neurodegenerative diseases that include Alzheimer’s, Parkinson’s and those based on prions. The fundamental chemical process is the aggregation of proteins into fibrils and plaques within the brain. The core of the fibrils from different proteins share a common atomic architecture known as cross-β spines that are formed by a pair of β-sheets whose side-chains interdigitate into a so-called dry steric zipper. The crystal structures for over 50 subsequences 4 to 10 amino acids in length, which are implicated in driving fibril formation, have recently been solved are available from the PDB. Preliminary studies for the polymorphs of the subsequence Asn-Asn-Gln-Gln (NNQQ) from yeast prion Sup35 have been examined using our unique combination of the polarizable AMOEBA force field and the OSRW sampling strategy implemented in the Force Field X program. Relative to the optimized peptide in vapor, the AMOEBA force field lattice potential energies for two minimized polymorphs are -193.3 and -204.0 kcal/mol for PDB IDs 2OLX and 2ONX, respectively. The free energy difference between the polymorphs is expected to be much less than 10.7 kcal/mol, since both are observed experimentally. We have shown that simulations not only predict the structures of the crystal polymorphs, but also nearly identical deposition free energy values of -86.6 ± 2.0 and -86.0 ± 2.0 for 2OLX and 2ONX, respectively (<b>Figure 1</b>). Sampling convergence required ~0.3-0.4 microseconds for these four residues peptides, and therefore longer simulation time scales are anticipated for 5-8 residue peptide systems. This motivates continued work to maximize sampling efficiency for the prediction of the structure and thermodynamics of polymer crystals described by polarizable atomic multipole force fields.

Structure and thermodynamics of peptide crystals from simulations with a polarizable force field

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.