Molecular Environment-Specific Atomic Charges Improve Binding Affinity Predictions of SAMPL5 Host-Guest Systems.
Duván GonzálezLuis MacayaEsteban Vöhringer-MartinezPublished in: Journal of chemical information and modeling (2021)
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.
Keyphrases
- molecular dynamics
- density functional theory
- molecular dynamics simulations
- dna binding
- water soluble
- single molecule
- binding protein
- machine learning
- monte carlo
- deep learning
- capillary electrophoresis
- computed tomography
- risk assessment
- magnetic resonance
- human health
- mass spectrometry
- ionic liquid
- electronic health record