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Molecular Dynamics Simulation of Tryptophan Hydroxylase-1: Binding Modes and Free Energy Analysis to Phenylalanine Derivative Inhibitors
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610041, China
These authors contributed equally to this work.
* Authors to whom correspondence should be addressed.
Received: 28 March 2013; in revised form: 27 April 2013 / Accepted: 6 May 2013 / Published: 10 May 2013
Abstract: Serotonin is a neurotransmitter that modulates many central and peripheral functions. Tryptophan hydroxylase-1 (TPH1) is a key enzyme of serotonin synthesis. In the current study, the interaction mechanism of phenylalanine derivative TPH1 inhibitors was investigated using molecular dynamics (MD) simulations, free energy calculations, free energy decomposition analysis and computational alanine scanning. The predicted binding free energies of these complexes are consistent with the experimental data. The analysis of the individual energy terms indicates that although the van der Waals and electrostatics interaction contributions are important in distinguishing the binding affinities of these inhibitors, the electrostatic contribution plays a more crucial role in that. Moreover, it is observed that different configurations of the naphthalene substituent could form different binding patterns with protein, yet lead to similar inhibitory potency. The combination of different molecular modeling techniques is an efficient way to interpret the interaction mechanism of inhibitors and our work could provide valuable information for the TPH1 inhibitor design in the future.
Keywords: tryptophan hydroxylase; phenylalanine derivative; molecular dynamics simulation; MM/GBSA
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Zhong, H.; Huang, W.; He, G.; Peng, C.; Wu, F.; Ouyang, L. Molecular Dynamics Simulation of Tryptophan Hydroxylase-1: Binding Modes and Free Energy Analysis to Phenylalanine Derivative Inhibitors. Int. J. Mol. Sci. 2013, 14, 9947-9962.
Zhong H, Huang W, He G, Peng C, Wu F, Ouyang L. Molecular Dynamics Simulation of Tryptophan Hydroxylase-1: Binding Modes and Free Energy Analysis to Phenylalanine Derivative Inhibitors. International Journal of Molecular Sciences. 2013; 14(5):9947-9962.
Zhong, Hao; Huang, Wei; He, Gu; Peng, Cheng; Wu, Fengbo; Ouyang, Liang. 2013. "Molecular Dynamics Simulation of Tryptophan Hydroxylase-1: Binding Modes and Free Energy Analysis to Phenylalanine Derivative Inhibitors." Int. J. Mol. Sci. 14, no. 5: 9947-9962.