<i>Ab initio </i>quantum mechanical (QM) calculations are being increasingly used to compute the structures and properties of large biomolecular systems, such as DNA or proteins. QM calculations on such species provide a much more accurate description of their physicochemical properties compared to the more routinely used force-field-based molecular mechanics (MM) methods. Unfortunately, the steep computational scaling of traditional quantum mechanical methods limits their applicability for large molecules. We have developed the Molecules-in-Molecules (MIM) fragment-based approach to overcome these bottlenecks and to enable accurate calculations on such systems.<br/>          In this work, a rigorous evaluation of the potential of the multilayer MIM fragmentation method to investigate large biomolecules is presented. A wide range of density functional methods are applied to a representative test set of polypeptides containing 100 to 800 atoms to help develop a MIM protocol for the treatment of large proteins. A number of different fragmentation schemes are tested to generate accurate energies for large molecules incorporating the contributions of all significant nonbonded interactions. To overcome any associated computational cost limitations, a 3-layer MIM method (MIM3) is presented for the first time, with a distance-based medium level of fragmentation and semi-empirical methods (e.g. PM6-D3H4) as the low level. Our protocol maintains modest-sized fragments in the high layer while still accurately including the long range interactions even for very large biomolecules. The total energy of peptide systems containing several hundreds of atoms can now be predicted with high accuracy (within 0-2 kcal/mol of the full calculation on the unfragmented molecule), but using substantially less computer time.

Assessment of fragmentation strategies for large proteins using the multilayer molecules-in-molecules (MIM) approach

256th National Meeting (2018)

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