On the Use of Interaction Entropy and Related Methods to Estimate Binding Entropies
(2021) In Journal of Chemical Theory and Computation 17(8). p.5379-5391- Abstract
Molecular mechanics combined with Poisson-Boltzmann or generalized Born and solvent-accessible area solvation energies (MM/PBSA and MM/GBSA) are popular methods to estimate the free energy for the binding of small molecules to biomacromolecules. However, the estimation of the entropy has been problematic and time-consuming. Traditionally, normal-mode analysis has been used to estimate the entropy, but more recently, alternative approaches have been suggested. In particular, it has been suggested that exponential averaging of the electrostatic and Lennard-Jones interaction energies may provide much faster and more accurate entropies, the interaction entropy (IE) approach. In this study, we show that this exponential averaging is... (More)
Molecular mechanics combined with Poisson-Boltzmann or generalized Born and solvent-accessible area solvation energies (MM/PBSA and MM/GBSA) are popular methods to estimate the free energy for the binding of small molecules to biomacromolecules. However, the estimation of the entropy has been problematic and time-consuming. Traditionally, normal-mode analysis has been used to estimate the entropy, but more recently, alternative approaches have been suggested. In particular, it has been suggested that exponential averaging of the electrostatic and Lennard-Jones interaction energies may provide much faster and more accurate entropies, the interaction entropy (IE) approach. In this study, we show that this exponential averaging is extremely poorly conditioned. Using stochastic simulations, assuming that the interaction energies follow a Gaussian distribution, we show that if the standard deviation of the interaction energies (σIE) is larger than 15 kJ/mol, it becomes practically impossible to converge the interaction entropies (more than 10 million energies are needed, and the number increases exponentially). A cumulant approximation to the second order of the exponential average shows a better convergence, but for σIE > 25 kJ/mol, it gives entropies that are unrealistically large. Moreover, in practical applications, both methods show a steady increase in the entropy with the number of energies considered.
(Less)
- author
- Ekberg, Vilhelm LU and Ryde, Ulf LU
- organization
- publishing date
- 2021-08
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Chemical Theory and Computation
- volume
- 17
- issue
- 8
- pages
- 13 pages
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- pmid:34254810
- scopus:85111188272
- ISSN
- 1549-9618
- DOI
- 10.1021/acs.jctc.1c00374
- language
- English
- LU publication?
- yes
- id
- a1a7ba90-4ac6-4147-99b3-5053977c8319
- date added to LUP
- 2021-12-27 13:46:14
- date last changed
- 2024-04-20 18:22:25
@article{a1a7ba90-4ac6-4147-99b3-5053977c8319, abstract = {{<p>Molecular mechanics combined with Poisson-Boltzmann or generalized Born and solvent-accessible area solvation energies (MM/PBSA and MM/GBSA) are popular methods to estimate the free energy for the binding of small molecules to biomacromolecules. However, the estimation of the entropy has been problematic and time-consuming. Traditionally, normal-mode analysis has been used to estimate the entropy, but more recently, alternative approaches have been suggested. In particular, it has been suggested that exponential averaging of the electrostatic and Lennard-Jones interaction energies may provide much faster and more accurate entropies, the interaction entropy (IE) approach. In this study, we show that this exponential averaging is extremely poorly conditioned. Using stochastic simulations, assuming that the interaction energies follow a Gaussian distribution, we show that if the standard deviation of the interaction energies (σIE) is larger than 15 kJ/mol, it becomes practically impossible to converge the interaction entropies (more than 10 million energies are needed, and the number increases exponentially). A cumulant approximation to the second order of the exponential average shows a better convergence, but for σIE > 25 kJ/mol, it gives entropies that are unrealistically large. Moreover, in practical applications, both methods show a steady increase in the entropy with the number of energies considered. </p>}}, author = {{Ekberg, Vilhelm and Ryde, Ulf}}, issn = {{1549-9618}}, language = {{eng}}, number = {{8}}, pages = {{5379--5391}}, publisher = {{The American Chemical Society (ACS)}}, series = {{Journal of Chemical Theory and Computation}}, title = {{On the Use of Interaction Entropy and Related Methods to Estimate Binding Entropies}}, url = {{http://dx.doi.org/10.1021/acs.jctc.1c00374}}, doi = {{10.1021/acs.jctc.1c00374}}, volume = {{17}}, year = {{2021}}, }