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ABSTRACT Voltage‐dependent anion channel (VDAC) is the primary conduit for regulated passage of ions and metabolites into and out of a mitochondrion. Calculating the solvation free energy for VDAC is crucial for understanding its stability, function, and interactions within the cellular environment. In this article, numerical schemes for computing the total solvation free energy for VDAC—comprising electrostatic, ideal gas, and excess free energies plus the nonpolar energy—are developed based on a nonuniform size modified Poisson–Boltzmann ion channel (nuSMPBIC) finite element solver along with tetrahedral meshes for VDAC proteins. The current mesh generation package is also updated to improve mesh quality and accelerate mesh generation. A VDAC Solvation Free Energy Calculation (VSFEC) package is then created by integrating these schemes with the updated mesh package, the nuSMPBIC finite element package, the PDB2PQR package, and the OPM database, as well as one uniform SMPBIC finite element package and one Poisson–Boltzmann ion channel (PBIC) finite element package. With the VSFEC package, many numerical experiments are made using six VDAC proteins, eight ionic solutions containing up to four ionic species, including ATP4−and Ca2+, two reference states, different boundary values, and different permittivity constants. The test results underscore the importance of considering nonuniform ionic size effects to explore the varying patterns of the total solvation free energy, and demonstrate the high performance of the VSFEC package for VDAC solvation free energy calculation.
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Development and test of highly accurate endpoint free energy methods. 1: Evaluation of ABCG2 charge model on solvation free energy prediction and optimization of atom radii suitable for more accurate solvation free energy prediction by the PBSA method
Abstract Accurate estimation of solvation free energy (SFE) lays the foundation for accurate prediction of binding free energy. The Poisson‐Boltzmann (PB) or generalized Born (GB) combined with surface area (SA) continuum solvation method (PBSA and GBSA) have been widely used in SFE calculations because they can achieve good balance between accuracy and efficiency. However, the accuracy of these methods can be affected by several factors such as the charge models, polar and nonpolar SFE calculation methods and the atom radii used in the calculation. In this work, the performance of the ABCG2 (AM1‐BCC‐GAFF2) charge model as well as other two charge models, that is, RESP (Restrained Electrostatic Potential) and AM1‐BCC (Austin Model 1‐bond charge corrections), on the SFE prediction of 544 small molecules in water by PBSA/GBSA was evaluated. In order to improve the performance of the PBSA prediction based on the ABCG2 charge, we further explored the influence of atom radii on the prediction accuracy and yielded a set of atom radius parameters for more accurate SFE prediction using PBSA based on the ABCG2/GAFF2 by reproducing the thermodynamic integration (TI) calculation results. The PB radius parameters of carbon, oxygen, sulfur, phosphorus, chloride, bromide and iodine, were adjusted. New atom types,on,oi,hn1,hn2,hn3, were introduced to further improve the fitting performance. Then, we tuned the parameters in the nonpolar SFE model using the experimental SFE data and the PB calculation results. By adopting the new radius parameters and new nonpolar SFE model, the root mean square error (RMSE) of the SFE calculation for the 544 molecules decreased from 2.38 to 1.05 kcal/mol. Finally, the new radius parameters were applied in the prediction of protein‐ligand binding free energies using the MM‐PBSA method. For the eight systems tested, we could observe higher correlation between the experiment data and calculation results and smaller prediction errors for the absolute binding free energies, demonstrating that our new radius parameters can improve the free energy calculation using the MM‐PBSA method.
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- Award ID(s):
- 1955260
- PAR ID:
- 10408607
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Journal of Computational Chemistry
- Volume:
- 44
- Issue:
- 14
- ISSN:
- 0192-8651
- Page Range / eLocation ID:
- p. 1334-1346
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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