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240510s2024 xx |||||o 00| ||eng c |
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|a 10.1002/jcc.27365
|2 doi
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|a pubmed24n1492.xml
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|a (DE-627)NLM372137970
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|a (NLM)38725239
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|a DE-627
|b ger
|c DE-627
|e rakwb
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| 041 |
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|a eng
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| 100 |
1 |
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|a Baumann, Hannah M
|e verfasserin
|4 aut
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| 245 |
1 |
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|a Impact of protein conformations on binding free energy calculations in the beta-secretase 1 system
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1 |
|c 2024
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|a Text
|b txt
|2 rdacontent
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|a ƒaComputermedien
|b c
|2 rdamedia
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| 338 |
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|a ƒa Online-Ressource
|b cr
|2 rdacarrier
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|a Date Completed 10.07.2024
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|a Date Revised 05.08.2024
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|a published: Print-Electronic
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|a Citation Status MEDLINE
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|a © 2024 Wiley Periodicals LLC.
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|a In binding free energy calculations, simulations must sample all relevant conformations of the system in order to obtain unbiased results. For instance, different ligands can bind to different metastable states of a protein, and if these protein conformational changes are not sampled in relative binding free energy calculations, the contribution of these states to binding is not accounted for and thus calculated binding free energies are inaccurate. In this work, we investigate the impact of different beta-sectretase 1 (BACE1) protein conformations obtained from x-ray crystallography on the binding of BACE1 inhibitors. We highlight how these conformational changes are not adequately sampled in typical molecular dynamics simulations. Furthermore, we show that insufficient sampling of relevant conformations induces substantial error in relative binding free energy calculations, as judged by a variation in calculated relative binding free energies up to 2 kcal/mol depending on the starting protein conformation. These results emphasize the importance of protein conformational sampling and pose this BACE1 system as a challenge case for further method development in the area of enhanced protein conformational sampling, either in combination with binding calculations or as an endpoint correction
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|a Journal Article
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|a RBFE
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|a beta‐secretase
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| 650 |
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4 |
|a binding free energy
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| 650 |
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4 |
|a conformational changes
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| 650 |
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4 |
|a molecular dynamics
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|a sampling problems
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|a Amyloid Precursor Protein Secretases
|2 NLM
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| 650 |
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|a EC 3.4.-
|2 NLM
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| 650 |
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|a Aspartic Acid Endopeptidases
|2 NLM
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| 650 |
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7 |
|a EC 3.4.23.-
|2 NLM
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| 650 |
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|a BACE1 protein, human
|2 NLM
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| 650 |
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7 |
|a EC 3.4.23.46
|2 NLM
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| 650 |
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7 |
|a Ligands
|2 NLM
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| 700 |
1 |
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|a Mobley, David L
|e verfasserin
|4 aut
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| 773 |
0 |
8 |
|i Enthalten in
|t Journal of computational chemistry
|d 1984
|g 45(2024), 23 vom: 05. Aug., Seite 2024-2033
|w (DE-627)NLM098138448
|x 1096-987X
|7 nnns
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| 773 |
1 |
8 |
|g volume:45
|g year:2024
|g number:23
|g day:05
|g month:08
|g pages:2024-2033
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| 856 |
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|u http://dx.doi.org/10.1002/jcc.27365
|3 Volltext
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