Sunday, April 14, 2013

Three- and four-body corrected fragment molecular orbital calculations with a novel subdividing fragmentation method applicable to structure-based drug design

Chiduru Watanabe, Kaori Fukuzawa, Yoshio Okiyama, Takayuki Tsukamoto, Akifumi Kato, Shigenori Tanaka, Yuji Mochizuki, and Tatsuya Nakano Journal of Molecular Graphics and Modelling 2013, 41, 31.
Contributed by +Jan Jensen

One of the advantages of fragmentation based electronic structure methods over conventional linear scaling method is that one gets an automatic energy analysis in terms of interfragment interaction energies (IFIEs).  When applied to protein-ligans interactions such IFIE analyses can aid in the drug design process.  

However, in order to obtain accurate results the whole ligand is often treated as one fragment and the contribution of individual ligand functional groups to the binding is lost.  A main reason that accuracy depends on fragment size is that as fragments get smaller, many-body short-range interaction energies such as exchange repulsion become important.  Most fragmentation methods only treat such effects at the two-body level, while the Fragment Molecular Orbital (FMO) method also has a three-body corrected version (FMO3).  Nakano et al. have recently developed a four-body version of the FMO4 which yields accurate total energies for functional group-sized fragments, and this study by Watanabe et al presents the corresponding IFIE analysis.

At the MP2/6-31G level of theory and using an FMO2 calculation using one residue per monomer as a reference, the accuracy and CPU cost is comparable to an FMO3 calculation if the fragment size is roughly halved.  The CPU increases only by a factor of three on going to FMO4, while the accuracy is increased by an order of magnitude.

The relatively modest increase in CPU time is due to the fact that the many-body short-range corrections only are computed for fragments in close proximity to one another. Thus, the number of corresponding trimer and tetramer calculations scale roughly linearly with system size.  I have explored the question of computational efficiency and fragment-size further in this post.

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