Molecular Dynamics Simulation of Tryptophan Hydroxylase-1: Binding Modes and Free Energy Analysis to Phenylalanine Derivative Inhibitors

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.

Ligand entry into the calyx of β‐lactoglobulin

“…This electrostatic behavior supports that observed through the analysis of the forces that stabilize the complex in GROMACS (Figure A–5C). In addition, formation of the macromolecular complexes is characterized by unfavorable entropy ( TΔS ) values due to a reduction in the translational, rotational, and vibrational degrees of freedom, as observed in other studies and also in this contribution. Although both complexes had similar entropy values, this analysis suggests a slightly higher conformational reduction upon complex formation for βlg–PA.…”

Fast, metadynamics‐based method for prediction of the stereochemistry‐dependent relative free energies of ligand–receptor interactions

“…Computations of based on MD simulations have a long history that can be traced back to the 1980s . Free‐energy calculations give insight into analysis of the structural features, and the stereoselective mechanism of physical and chemical processes, for example, reaction pathway, stereoselective catalysis, hydroxylation, selective complexation, polymerization, and ligand binding …”

Selective Docking of Pyranooxazoles Against nsP2 of CHIKV Eluted Through Isothermally and Non‐Isothermally MD simulations

“…The total numbers of average hydrogen bonds are formed during MD simulations in each time frame were represent in Figure , 14, 15, 16 and 17 . The average number of hydrogen bonds per drug molecule during 20 ns MD simulations at different temperature cutoffs at 2.82 (strong bonding) with a larger average angle . Further, there is a need to check the hydrogen bonds between the first five residues: ILE_270@O, ASN_307@O, CYS_271@O, ARG_306@O and GLY_274@H. It is considered that a hydrogen bond formed when the distance between residue oxygen O in the backbone with nitrogen and hydrogen atom in the drug molecules is shorter (2.82 Å) and the angle of N−H‐O is 143.82°.…”