Mechanisms for Benzene Dissociation through the Excited State of T4 Lysozyme L99A Mutant
| Autor: | Rommie E. Amaro, Nathan Mih, Daniel J. Mermelstein, Victoria A. Feher, J. Andrew McCammon, Levi C. T. Pierce, Jamie M. Schiffer |
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| Rok vydání: | 2018 |
| Předmět: |
Mutant
Static Electricity Biophysics Molecular Dynamics Simulation Dissociation (chemistry) 03 medical and health sciences chemistry.chemical_compound Molecular dynamics 0302 clinical medicine Static electricity 030304 developmental biology 0303 health sciences Binding Sites Wild type Benzene Articles Biological Sciences Molecular Docking Simulation chemistry Amino Acid Substitution Chemical physics Excited state Physical Sciences Chemical Sciences Muramidase Lysozyme Ground state 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Biophysical journal, vol 116, iss 2 |
| ISSN: | 1542-0086 |
| Popis: | The atomic-level mechanisms that coordinate ligand release from protein pockets are only known for a handful of proteins. Here, we report results from accelerated molecular dynamics simulations for benzene dissociation from the buried cavity of the T4 lysozyme Leu99Ala mutant (L99A). In these simulations, benzene is released through a previously characterized, sparsely populated room-temperature excited state of the mutant, explaining the coincidence for experimentally measured benzene off rate and apo protein slow-timescale NMR relaxation rates between ground and excited states. The path observed for benzene egress is a multistep ligand migration from the buried cavity to ultimate release through an opening between the F/G-, H-, and I-helices and requires a number of cooperative multiresidue and secondary-structure rearrangements within the C-terminal domain of L99A. These rearrangements are identical to those observed along the ground state to excited state transitions characterized by molecular dynamic simulations run on the Anton supercomputer. Analyses of the molecular properties of the residues lining the egress path suggest that protein surface electrostatic potential may play a role in the release mechanism. Simulations of wild-type T4 lysozyme also reveal that benzene-egress-associated dynamics in the L99A mutant are potentially exaggerations of the substrate-processivity-related dynamics of the wild type. |
| Databáze: | OpenAIRE |
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