Recent developments in the fragment molecular orbital (FMO) method for theoretical formulation, implementation, and application to nano and biomolecular systems are reviewed. The FMO method has enabled ab initio quantum-mechanical calculations for large molecular systems such as protein-ligand complexes at a reasonable computational cost in a parallelized way. There have been a wealth of application outcomes from the FMO method in the fields of biochemistry, medicinal chemistry and nanotechnology, in which the electron correlation effects play vital roles. With the aid of the advances in high-performance computing, the FMO method promises larger, faster, and more accurate simulations of biomolecular and related systems, including the descriptions of dynamical behaviors in solvent environments. The current status and future prospects of the FMO scheme are addressed in these contexts.

The worldwide spread of COVID-19 (new coronavirus found in 2019) is an emergent issue to be tackled. In fact, a great amount of works in various fields have been made in a rather short period. Here, we report a fragment molecular orbital (FMO) based interaction analysis on a complex between the SARS-CoV-2 main protease (Mpro) and its peptide-like inhibitor N3 (PDB ID: 6LU7). The target inhibitor molecule was segmented into five fragments in order to capture site specific interactions with amino acid residues of the protease. The interaction energies were decomposed into several contributions, and then the characteristics of hydrogen bonding and dispersion stabilization were made clear. Furthermore, the hydration effect was incorporated by the Poisson–Boltzmann (PB) scheme. From the present FMO study, His41, His163, His164, and Glu166 were found to be the most important amino acid residues of Mpro in interacting with the inhibitor, mainly due to hydrogen bonding. A guideline for optimizations of the inhibitor molecule was suggested as well based on the FMO analysis.

Due to the COVID-19 pandemic, researchers have attempted to identify complex structures of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (S-protein) with angiotensin-converting enzyme 2 (ACE2) or...

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Significant activity changes due to small structural changes (i.e., activity cliffs) of serine/threonine kinase Pim1 inhibitors were studied theoretically using the fragment molecular orbital method with molecular mechanics Poisson-Boltzmann surface area (FMO+MM-PBSA) approach. This methodology enables quantum-chemical calculations for large biomolecules with solvation. In the course of drug discovery targeting Pim1, six benzofuranone-class inhibitors were found to differ only in the position of the indole-ring nitrogen atom. By comparing the various qualities of complex structures based on X-ray, classical molecular mechanics (MM)-optimized, and quantum/molecular mechanics (QM/MM)-optimized structures, we found that the QM/MM-optimized structures provided the best correlation (R = 0.85) between pIC and the calculated FMO+MM-PBSA binding energy. Combining the classical solvation energy with the QM binding energy was important to increase the correlation. In addition, decomposition of the interaction energy into various physicochemical components by pair interaction energy decomposition analysis suggested that CH-π and electrostatic interactions mainly caused the activity differences.