Molecular Environment-Specific Atomic Charges Improve Binding Affinity Predictions of SAMPL5 Host–Guest Systems

Abstract

Host−guest systems are widely used in benchmarks as model systems to improve computational methods for absolute binding free energy predictions. Recent advances in sampling algorithms for alchemical free energy calculations and the increase in computational power have made their binding affinity prediction primarily dependent on the quality of the force field.Here, we propose a new methodology to derive the atomic charges of host−guest systems based on quantum mechanics/molecular mechanics calculations and minimal basis iterative stockholder (MBIS) partitioning of the polarized electron density. A newly developed interface between the OpenMM and ORCA software packages provides D-MBIS charges that represent the guest's average electrostatic interactions in the hosts or the solvent. The simulation workflow also calculates the average energy required to polarize the guest in the bound and unbound state. Alchemical free energy calculations using the general Amber force field parameters with D-MBIS charges improve the binding affinity prediction of six guests bound to two octa acid hosts compared to the AM1-BCC charge set after correction with the average energetic polarization cost. This correction originates from the difference in potential energy that is required to polarize the guest in the bound and unbound state and contributes significantly to the binding affinity of anionic guests.

Nonbonded Force Field Parameters from Minimal Basis Iterative Stockholder Partitioning of the Molecular Electron Density Improve CB7 Host–Guest Affinity Predictions

“…The polarization of the guest in the host in comparison to the noninteracting isolated guest is associated with a potential energy cost that is always positive. Because the binding free energy calculations employ a double decoupling scheme, this polarization energy would cancel out only if it would be the same in the bound state and the solvent; but as we have shown previously, the polarization energy cost differs between the two molecular environments . This difference between environments contributes to the binding free energy and is usually neglected in absolute binding free energy calculations with nonpolarizable force fields.…”

“…To calculate the D-MBIS atomic charges, the host was surrounded by water molecules and ions required to emulate the ionic strength. Our simulation protocol in Python combines molecular dynamics simulation carried out with OpenMM with the QM/MM methodology applied to several configurations of the trajectory. Electron densities were obtained with the QM/MM method at the B3LYP level of theory with the def2-TZVP basis set, , using the new support to import force fields combined with PDB files in ORCA 4.2.1 in which all MM atoms are included as point charges.…”

“…This approach is similar to our previously proposed method using an implicit representation of the electrostatic reaction field of the solvent together with the MBIS partitioning method but neglects the potential energy required to polarize the solute’s electron density in the transfer from the gas to the condensed phase. We have shown recently that this contribution becomes important for anionic guest in the octa acid hosts …”

DFT-D4 Insight into the Inclusion of Amphetamine and Methamphetamine in Cucurbit[7]uril: Energetic, Structural and Biosensing Properties

“…Then, the computational process followed to calculate the most stable configurations (configurations of minimum energy) corresponding to the inclusion complexes of AMP and MET with CB [7] was based on the method developed by Liu and Guo [54]. In addition to Liu and Guo method, other techniques have been developed recently for the theoretical modelling of host-guest binding affinity [55][56][57][58][59][60]. Liu and Guo proposed the semi-empirical methods such as AM1 and PM3, which are fast and could be applied for several positions along the z-axis.…”

Does Hamiltonian Replica Exchange via Lambda-Hopping Enhance the Sampling in Alchemical Free Energy Calculations?

“…In Ref. [ 17 ], convergence in HREM-based approaches was found sluggish even in simple host–guest systems [ 18 ], requiring a “significant number of iterations”. A similar outcome was found in the 2022 study by Markthaler et al [ 19 ], where rather long (more than 100 ns) HREM simulations were required to “remove an observed starting structure dependence to an acceptable results”.…”