skip to main content


Title: CHARMM-GUI Free Energy Calculator for Absolute and Relative Ligand Solvation and Binding Free Energy Simulations
Award ID(s):
1810695 1660380
NSF-PAR ID:
10229939
Author(s) / Creator(s):
; ; ; ; ; ; ; ; ;
Date Published:
Journal Name:
Journal of Chemical Theory and Computation
Volume:
16
Issue:
11
ISSN:
1549-9618
Page Range / eLocation ID:
7207 to 7218
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. 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.

     
    more » « less
  2. Many biomolecules undergo conformational changes associated with allostery or ligand binding. Observing these changes in computer simulations is difficult if their timescales are long. These calculations can be accelerated by observing the transition on an auxiliary free energy surface with a simpler Hamiltonian and connecting this free energy surface to the target free energy surface with free energy calculations. Here, we show that the free energy legs of the cycle can be replaced with energy representation (ER) density functional approximations. We compute: (1) The conformational free energy changes for alanine dipeptide transitioning from the right‐handed free energy basin to the left‐handed basin and (2) the free energy difference between the open and closed conformations ofβ‐cyclodextrin, a “host” molecule that serves as a model for molecular recognition in host‐guest binding.β‐cyclodextrin contains 147 atoms compared to 22 atoms for alanine dipeptide, makingβ‐cyclodextrin a large molecule for which to compute solvation free energies by free energy perturbation or integration methods and the largest system for which the ER method has been compared to exact free energy methods. The ER method replaced the 28 simulations to compute each coupling free energy with two endpoint simulations, reducing the computational time for the alanine dipeptide calculation by about 70% and for theβ‐cyclodextrin by > 95%. The method works even when the distribution of conformations on the auxiliary free energy surface differs substantially from that on the target free energy surface, although some degree of overlap between the two surfaces is required. © 2016 Wiley Periodicals, Inc.

     
    more » « less
  3. Abstract

    The mass-loss rates from single massive stars are high enough to form radio photospheres at large distances from the stellar surface, where the wind is optically thick to (thermal) free–free opacity. Here we calculate the far-infrared, millimeter, and radio band spectral energy distributions (SEDs) that can result from the combination of free–free processes and synchrotron emission, to explore the conditions for nonthermal SEDs. Simplifying assumptions are adopted in terms of scaling relations for the magnetic field strength and the spatial distribution of relativistic electrons. The wind is assumed to be spherically symmetric, and we consider the effect of Razin suppression on the synchrotron emission. Under these conditions, long-wavelength SEDs with synchrotron emission can be either more steep or more shallow than the canonical asymptotic power-law SED from a nonmagnetic wind. When nonthermal emission is present, the resultant SED shape is generally not a power law; however, the variation in the slope can change slowly with wavelength. Consequently, over a limited range of wavelengths, the SED can masquerade as approximately a power law. While most observed nonthermal long-wavelength spectra are associated with binarity, synchrotron emission can have only a mild influence on single-star SEDs, requiring finer levels of wavelength sampling for the detection of the effect.

     
    more » « less