In silico concurrent multisite pH titration in proteins
Copyright © 2014 Wiley Periodicals, Inc.
| Veröffentlicht in: | Journal of computational chemistry. - 1984. - 35(2014), 20 vom: 30. Juli, Seite 1491-8 |
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| Format: | Online-Aufsatz |
| Sprache: | English |
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2014
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| Zugriff auf das übergeordnete Werk: | Journal of computational chemistry |
| Schlagworte: | Journal Article Research Support, Non-U.S. Gov't generalized ensemble grand canonical ensemble mean field multistate free energy perturbation Protons Aspartic Acid 30KYC7MIAI Glutamic Acid mehr... |
| Zusammenfassung: | Copyright © 2014 Wiley Periodicals, Inc. The concurrent proton binding at multiple sites in macromolecules such as proteins and nucleic acids is an important yet challenging problem in biochemistry. We develop an efficient generalized Hamiltonian approach to attack this issue. Based on the previously developed generalized-ensemble methods, an effective potential energy is constructed which combines the contributions of all (relevant) protonation states of the molecule. The effective potential preserves important phase regions of all states and, thus, allows efficient sampling of these regions in one simulation. The need for intermediate states in alchemical free energy simulations is greatly reduced. Free energy differences between different protonation states can be determined accurately and enable one to construct the grand canonical partition function. Therefore, the complicated concurrent multisite proton titration process of protein molecules can be satisfactorily simulated. Application of this method to the simulation of the pKa of Glu49, Asp50, and C-terminus of bovine pancreatic trypsin inhibitor shows reasonably good agreement with published experimental work. This method provides an unprecedented vivid picture of how different protonation states change their relative population upon pH titration. We believe that the method will be very useful in deciphering the molecular mechanism of pH-dependent biomolecular processes in terms of a detailed atomistic description |
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| Beschreibung: | Date Completed 11.05.2015 Date Revised 25.06.2014 published: Print-Electronic Citation Status MEDLINE |
| ISSN: | 1096-987X |
| DOI: | 10.1002/jcc.23645 |