Recent Developments in Linear Interaction Energy Based Binding Free Energy Calculations
The linear interaction energy (LIE) approach is an end–point method to compute binding affinities. As such it combines explicit conformational sampling (of the protein-bound and unbound-ligand states) with efficiency in calculating values for the protein-ligand binding free energy ΔGbind. This persp...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-06-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fmolb.2020.00114/full |
| _version_ | 1818267090007621632 |
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| author | Eko Aditya Rifai Marc van Dijk Daan P. Geerke |
| author_facet | Eko Aditya Rifai Marc van Dijk Daan P. Geerke |
| author_sort | Eko Aditya Rifai |
| collection | DOAJ |
| description | The linear interaction energy (LIE) approach is an end–point method to compute binding affinities. As such it combines explicit conformational sampling (of the protein-bound and unbound-ligand states) with efficiency in calculating values for the protein-ligand binding free energy ΔGbind. This perspective summarizes our recent efforts to use molecular simulation and empirically calibrated LIE models for accurate and efficient calculation of ΔGbind for diverse sets of compounds binding to flexible proteins (e.g., Cytochrome P450s and other proteins of direct pharmaceutical or biochemical interest). Such proteins pose challenges on ΔGbind computation, which we tackle using a previously introduced statistically weighted LIE scheme. Because calibrated LIE models require empirical fitting of scaling parameters, they need to be accompanied with an applicability domain (AD) definition to provide a measure of confidence for predictions for arbitrary query compounds within a reference frame defined by a collective chemical and interaction space. To enable AD assessment of LIE predictions (or other protein-structure and -dynamic based ΔGbind calculations) we recently introduced strategies for AD assignment of LIE models, based on simulation and training data only. These strategies are reviewed here as well, together with available tools to facilitate and/or automate LIE computation (including software for combined statistically-weighted LIE calculations and AD assessment). |
| first_indexed | 2024-12-12T20:17:04Z |
| format | Article |
| id | doaj.art-64b02770dffb46aa92727a2d3e6f1518 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-12-12T20:17:04Z |
| publishDate | 2020-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-64b02770dffb46aa92727a2d3e6f15182022-12-22T00:13:21ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2020-06-01710.3389/fmolb.2020.00114519359Recent Developments in Linear Interaction Energy Based Binding Free Energy CalculationsEko Aditya RifaiMarc van DijkDaan P. GeerkeThe linear interaction energy (LIE) approach is an end–point method to compute binding affinities. As such it combines explicit conformational sampling (of the protein-bound and unbound-ligand states) with efficiency in calculating values for the protein-ligand binding free energy ΔGbind. This perspective summarizes our recent efforts to use molecular simulation and empirically calibrated LIE models for accurate and efficient calculation of ΔGbind for diverse sets of compounds binding to flexible proteins (e.g., Cytochrome P450s and other proteins of direct pharmaceutical or biochemical interest). Such proteins pose challenges on ΔGbind computation, which we tackle using a previously introduced statistically weighted LIE scheme. Because calibrated LIE models require empirical fitting of scaling parameters, they need to be accompanied with an applicability domain (AD) definition to provide a measure of confidence for predictions for arbitrary query compounds within a reference frame defined by a collective chemical and interaction space. To enable AD assessment of LIE predictions (or other protein-structure and -dynamic based ΔGbind calculations) we recently introduced strategies for AD assignment of LIE models, based on simulation and training data only. These strategies are reviewed here as well, together with available tools to facilitate and/or automate LIE computation (including software for combined statistically-weighted LIE calculations and AD assessment).https://www.frontiersin.org/article/10.3389/fmolb.2020.00114/fullbinding affinity computationfree energy calculationmolecular simulationlinear interaction energyprotein flexibilitybinding promiscuity |
| spellingShingle | Eko Aditya Rifai Marc van Dijk Daan P. Geerke Recent Developments in Linear Interaction Energy Based Binding Free Energy Calculations Frontiers in Molecular Biosciences binding affinity computation free energy calculation molecular simulation linear interaction energy protein flexibility binding promiscuity |
| title | Recent Developments in Linear Interaction Energy Based Binding Free Energy Calculations |
| title_full | Recent Developments in Linear Interaction Energy Based Binding Free Energy Calculations |
| title_fullStr | Recent Developments in Linear Interaction Energy Based Binding Free Energy Calculations |
| title_full_unstemmed | Recent Developments in Linear Interaction Energy Based Binding Free Energy Calculations |
| title_short | Recent Developments in Linear Interaction Energy Based Binding Free Energy Calculations |
| title_sort | recent developments in linear interaction energy based binding free energy calculations |
| topic | binding affinity computation free energy calculation molecular simulation linear interaction energy protein flexibility binding promiscuity |
| url | https://www.frontiersin.org/article/10.3389/fmolb.2020.00114/full |
| work_keys_str_mv | AT ekoadityarifai recentdevelopmentsinlinearinteractionenergybasedbindingfreeenergycalculations AT marcvandijk recentdevelopmentsinlinearinteractionenergybasedbindingfreeenergycalculations AT daanpgeerke recentdevelopmentsinlinearinteractionenergybasedbindingfreeenergycalculations |