+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Charges for Large Scale Binding Free Energy Calculations with the Linear Interaction Energy Method



Charges for Large Scale Binding Free Energy Calculations with the Linear Interaction Energy Method



Journal of Chemical Theory and Computation 5(2): 380-395



The linear interaction energy method (LIE), which combines force field based molecular dynamics (MD) simulations and linear response theory, has previously been shown to give fast and reliable estimates of ligand binding free energies, suggesting that this type of technique could be used also in a high-throughput fashion. However, a limiting step in such applications is the assignment of atomic charges for compounds that have not been parametrized within the given force field, in this case OPLS-AA. In order to reach an automatable solution to this problem, we have examined the performance of nine different ab initio and semiempirical charge methods, together with estimates of solvent induced polarization. A test set of ten HIV-1 reverse transcriptase inhibitors was selected, and LIE estimates of their relative binding free energies were calculated using the resulting 23 different charge variants. Over 800 ns of MD simulation show that the LIE method provides excellent estimates with several different charge methods and that the semiempirically derived CM1A charges, in particular, emerge as a fast and reliable alternative for fully automated LIE based virtual screens with the OPLS-AA force field. Our conclusions regarding different charge models are also expected to be valid for other types of force field based binding free energy calculations, such as free energy perturbation and thermodynamic integration simulations.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 057392481

Download citation: RISBibTeXText

PMID: 26610112

DOI: 10.1021/ct800404f


Related references

Are automated molecular dynamics simulations and binding free energy calculations realistic tools in lead optimization? An evaluation of the linear interaction energy (LIE) method. Journal of Chemical Information and Modeling 46(5): 1972-1983, 2006

In silico binding free energy predictability by using the linear interaction energy (LIE) method: bromobenzimidazole CK2 inhibitors as a case study. Journal of Chemical Information and Modeling 47(2): 572-582, 2007

Quantitative calculations of antibody--antigen binding: steroid--DB3 binding energies by the linear interaction energy method. Journal of Organic Chemistry 66(9): 3021-3026, 2001

Absolute and relative binding free energy calculations of the interaction of biotin and its analogs with streptavidin using molecular dynamics/free energy perturbation approaches. Proteins 16(3): 226-245, 1993

Efficient free energy calculations on small molecule host-guest systems - a combined linear interaction energy/one-step perturbation approach. Journal of Computational Chemistry 30(2): 212-221, 2009

Virtual screening of integrase inhibitors by large scale binding free energy calculations: the SAMPL4 challenge. Journal of Computer-Aided Molecular Design 28(4): 475-490, 2014

Large scale free energy calculations for blind predictions of protein-ligand binding: the D3R Grand Challenge 2015. Journal of Computer-Aided Molecular Design 30(9): 743-751, 2016

Estimation of the binding free energy by Linear Interaction Energy models. Mini Reviews in Medicinal Chemistry 12(6): 551-561, 2012

Estimation of the Binding Free Energy by Linear Interaction Energy Models. Mini-Reviews in Medicinal Chemistry 12(6): 551-561, 2012

The linear interaction energy method for predicting ligand binding free energies. Combinatorial Chemistry and High Throughput Screening 4(8): 613-626, 2001

Applying linear interaction energy method for binding affinity calculations of podophyllotoxin analogues with tubulin using continuum solvent model and prediction of cytotoxic activity. Journal of Molecular Graphics and Modelling 27(8): 930-943, 2009

Binding free energy predictions of farnesoid X receptor (FXR) agonists using a linear interaction energy (LIE) approach with reliability estimation: application to the D3R Grand Challenge 2. Journal of Computer-Aided Molecular Design 32(1): 239-249, 2018

Application of the linear interaction energy method (LIE) to estimate the binding free energy values of Escherichia coli wild-type and mutant arginine repressor C-terminal domain (ArgRc)-l-arginine and ArgRc-l-citrulline protein-ligand complexes. Journal of Molecular Graphics and Modelling 22(4): 249-262, 2004

What determines the van der Waals coefficient β in the LIE (linear interaction energy) method to estimate binding free energies using molecular dynamics simulations?. Proteins: Structure, Function, and Bioinformatics 34(3): 395-402, 1999

What determines the van der Waals coefficient beta in the LIE (linear interaction energy) method to estimate binding free energies using molecular dynamics simulations?. Proteins 34(3): 395-402, 1999