Comparison of the Efficiency of the LIE and MM/GBSA Methods to Calculate LigandBinding Energies
(2011) In Journal of Chemical Theory and Computation 7(11). p.37683778 Abstract
 We have evaluated the efficiency of two popular endpoint methods to calculate ligandbinding free energies, LIE (linear interaction energy) and MM/GBSA (molecular mechanics with generalized Born surfacearea solvation), i.e. the computational effort needed to obtain estimates of a similar precision. As a test case, we use the binding of seven biotin analogues to avidin. The energy terms used by MM/GBSA and LIE exhibit a similar correlation time (similar to 5 ps), and the equilibration time seems also to be similar, although it varies much between the various ligands. The results show that the LIE method is more effective than MM/GBSA, by a factor of 27 for a truncated spherical system with a radius of 26 angstrom and by a factor of... (More)
 We have evaluated the efficiency of two popular endpoint methods to calculate ligandbinding free energies, LIE (linear interaction energy) and MM/GBSA (molecular mechanics with generalized Born surfacearea solvation), i.e. the computational effort needed to obtain estimates of a similar precision. As a test case, we use the binding of seven biotin analogues to avidin. The energy terms used by MM/GBSA and LIE exhibit a similar correlation time (similar to 5 ps), and the equilibration time seems also to be similar, although it varies much between the various ligands. The results show that the LIE method is more effective than MM/GBSA, by a factor of 27 for a truncated spherical system with a radius of 26 angstrom and by a factor of 1.02.4 for the full avidin tetramer (radius 47 angstrom). The reason for this is the cost for the MM/GBSA entropy calculations, which more than compensates for the extra simulation of the free ligand in LIE. On the other hand, LIE requires that the protein is neutralized, whereas MM/GBSA has no such requirements. Our results indicate that both the truncation and neutralization of the proteins may slow the convergence and emphasize small differences in the calculations, e.g., differences between the four subunits in avidin. Moreover, LIE cannot take advantage of the fact that avidin is a tetramer. For this test case, LIE gives poor results with the standard parametrization, but after optimizing the scaling factor of the van der Waals terms, reasonable binding affinities can be obtained, although MM/GBSA still gives a significantly better predictive index and correlation to the experimental affinities. (Less)
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http://lup.lub.lu.se/record/2253249
 author
 Genheden, Samuel ^{LU} and Ryde, Ulf ^{LU}
 organization
 publishing date
 2011
 type
 Contribution to journal
 publication status
 published
 subject
 in
 Journal of Chemical Theory and Computation
 volume
 7
 issue
 11
 pages
 3768  3778
 publisher
 The American Chemical Society
 external identifiers

 wos:000296597300032
 scopus:80755155952
 ISSN
 15499618
 DOI
 10.1021/ct200163c
 language
 English
 LU publication?
 yes
 id
 75d4a8eaee644118b0306f4916ce29ce (old id 2253249)
 date added to LUP
 20111221 14:59:23
 date last changed
 20180107 03:49:14
@article{75d4a8eaee644118b0306f4916ce29ce, abstract = {We have evaluated the efficiency of two popular endpoint methods to calculate ligandbinding free energies, LIE (linear interaction energy) and MM/GBSA (molecular mechanics with generalized Born surfacearea solvation), i.e. the computational effort needed to obtain estimates of a similar precision. As a test case, we use the binding of seven biotin analogues to avidin. The energy terms used by MM/GBSA and LIE exhibit a similar correlation time (similar to 5 ps), and the equilibration time seems also to be similar, although it varies much between the various ligands. The results show that the LIE method is more effective than MM/GBSA, by a factor of 27 for a truncated spherical system with a radius of 26 angstrom and by a factor of 1.02.4 for the full avidin tetramer (radius 47 angstrom). The reason for this is the cost for the MM/GBSA entropy calculations, which more than compensates for the extra simulation of the free ligand in LIE. On the other hand, LIE requires that the protein is neutralized, whereas MM/GBSA has no such requirements. Our results indicate that both the truncation and neutralization of the proteins may slow the convergence and emphasize small differences in the calculations, e.g., differences between the four subunits in avidin. Moreover, LIE cannot take advantage of the fact that avidin is a tetramer. For this test case, LIE gives poor results with the standard parametrization, but after optimizing the scaling factor of the van der Waals terms, reasonable binding affinities can be obtained, although MM/GBSA still gives a significantly better predictive index and correlation to the experimental affinities.}, author = {Genheden, Samuel and Ryde, Ulf}, issn = {15499618}, language = {eng}, number = {11}, pages = {37683778}, publisher = {The American Chemical Society}, series = {Journal of Chemical Theory and Computation}, title = {Comparison of the Efficiency of the LIE and MM/GBSA Methods to Calculate LigandBinding Energies}, url = {http://dx.doi.org/10.1021/ct200163c}, volume = {7}, year = {2011}, }