H-Bonding Cooperativity Effects in Amyloids: Quantum Mechanical and Molecular Mechanics Study

The cooperativity effects have been evaluated on three model systems, the formamide, (formylamino)acetamide and amyloidic-layer oligomers with an increasing size of the monomer units (6, 13 and 214 atoms). In the last model, each layer is a dimer of the amino-acid sequence GNNQQNY in one-letter amino-acid abbreviations. The series of oligomers for each model system of up to six monomers have been constructed. For the calculation of the strength of a particular H-bond formed between various sub-oligomers within an oligomer, different wave function, density functional and semi-empirical quantum mechanical methods as well as empirical force fields have been used. Semi-empirical methods are found to be a reasonable compromise between accuracy and computational cost. These methods are able to describe the cooperativity effects with an accuracy almost comparable to that of the ab initio methods. On the contrary, the empirical force-field methods for all of the model systems mostly failed to describe the H-bonding cooperativity effects properly. Based on the results obtained in this work, we recommend using semi-empirical methods. For the systems where this is impossible, we agree to use polarizable force fields with some reservations. Generally, the more flexible the oligomer chain is (the less steric the repulsion or rigid motifs are), the larger the cooperativity that can be achieved. With the increasing number of monomers in a sequence connected via H-bonds, the cooperativity effects appear to be growing, but relatively soon (at 3-4 monomer units) they tend to become saturated.