Fragment Molecular Orbital Based Affinity Prediction toward Pyruvate Dehydrogenase Kinases: Insights into the Charge Transfer in Hydrogen Bond Networks

Abstract

The fragment molecular orbital (FMO) method is a fast quantum-mechanics method that divides systems into pieces of fragments and performs ab initio calculations. The method has been expected to improve the accuracy of describing protein-ligand interactions by incorporating electronic effects. In this article, FMO calculation with solvation methods were applied to the affinity prediction at the ATP-binding site of PDHK4. As the ionized aspartic acid lies at the center and is involved in the complex hydrogen bond networks, this system has turned out to be a difficult target to describe by traditional molecular-mechanics method. In the FMO calculation with the polarizable continuum model (PCM) solvation method, a considerable amount of charge ( 0.27e) was transferred from the ionized aspartate to the surrounding residues. We found that using FMO with the PCM solvation method was important to increase the correlation, and by incorporating the ligand deformation energy, the correlation was improved to R 0.81 for whole twelve compounds and R 0.91 without one outlier compound.

Use of caps in the auxiliary basis set formulation of the fragment molecular orbital method

“…In the applications of FMO to molecular binding, only PIEs of unconnected dimers are commonly used. 34,35 F I G U R E 1 Cancellation of cap energies (A) for an unconnected dimer and (B) in a connected dimer, resulting in a remainder for the connecting bond.…”

“…For unconnected dimers without a detached covalent bond between the two monomers, the effect of caps cancels out (see Figure 1) because each cap in a dimer IJ is present in one of the two monomers I or J . In the applications of FMO to molecular binding, only PIEs of unconnected dimers are commonly used 34,35 …”

Binding Free Energy Calculation Based on the Fragment Molecular Orbital Method and Its Application in Designing Novel SHP-2 Allosteric Inhibitors

“…Solvation effects should be taken into consideration when assessing binding affinities, particularly in cases involving interactions with ionized fragments [ 34 ]. In recent years, solvation methods have been incorporated into the FMO method through the utilization of implicit solvent models such as the polarized continuum model (PCM) and solvation model density (SMD) [ 35 , 36 , 37 , 38 , 39 ]. In addition, the solvation energies were calculated in separate calculations using generalized Born/surface area (GBSA) or the Poisson–Boltzmann/surface area (PBSA) method [ 40 , 41 , 42 , 43 ].…”

“…Hence, we intend to assess the performance of three levels of implicit solvent models (ab initio, semi-empirical, and molecular mechanics (MM)-based) on FMO binding affinity calculations using the Schrödinger FEP+ data set [ 48 ] as a benchmark. Currently, studies have reported that the incorporation of ligand deformation energy can enhance the predictive performance of the FMO /PCM method in binding affinity predictions [ 36 , 49 ]. However, as of now, there is no reported research on the contribution of entropy.…”

“…13 C NMR (151 MHz, DMSO-d 6 ) δ 156 36,. 146.68, 141.50, 139.72, 130.42, 127.62, 127.57, 126.81, 125.78, 119.41, 119.30, 114.88, 114.74, 106.12, 45.89, 43.62, 29.61.…”