Insights into Exogenous Tryptophan-Mediated Allosteric Communication and Helical Transition of TRP Protein for Transcription Regulation

• Published in: Journal of chemical information and modeling Vol. 60; no. 1; pp. 175 - 191
• Main Authors: Mariadasse, Richard, Choubey, Sanjay Kumar, Jeyakanthan, Jeyaraman
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 27-01-2020
• Subjects: Allosteric Regulation; Amino acids; Arginine - chemistry; Binding energy; Binding sites; Catalytic Domain; Complex formation; Density Functional Theory; Deoxyribonucleic acid; DNA; DNA - chemistry; DNA-Binding Proteins - chemistry; Free energy; Grooves; Molecular docking; Molecular dynamics; Nucleic Acid Conformation; Poisson Distribution; Protein Binding; Protein Conformation; Proteins; Recognition; Regulatory mechanisms (biology); Sequence Alignment; Structural integrity; Transcription Factors - chemistry; Transcription, Genetic; Tryptophan; Tryptophan - chemistry; Variation
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/acs.jcim.9b00755

In this study, the binding recognition and allosteric mechanism of tryptophan-responsive regulatory protein (TRP)–DNA and bound exogenous tryptophan (Trp) amino acid complexes for transcriptional regulation were explained through the molecular docking, molecular dynamics (MD), free-energy landscape (FEL), binding free energy (molecular mechanics Poisson–Boltzmann surface area, MMPBSA), and protein structural network (PSN) analyses. The domain transition of helix–turn–helix (HTH) and effector binding domain (EBD) of TRP protein is the vital process for allosteric network communication, DNA recognition, and transcription. TRP protein consists of four putative active site pockets (Act1, Act2, Act3, and Act4) with the binding specificity of exogenous Trp amino acid, which modulates the binding energy of TRP–DNA complexes by conferring the specific residual network and internal helical orientation of DNA-binding domain (DBD) for regulatory mechanism. In the TRP–DNA complex, interaction of Arg28 (helix-1) and Arg36 (helix-2) with the DNA molecule plays a vital role in DNA recognition. As a consequence, allosteric induction of exogenous Trp in the Act3 binding site retains the structural integrity and is quite comfortable with DNA major groove; therefore, it produces less binding energy for complex formation and may involve in oligomeric association for transcription regulation. Meanwhile, Trp in the Act1 binding site induces high helical orientation and fluctuations, leading to dissociation of DNA from the TRP protein. The remaining two complexes of Trp with Act2 and Act4 are predicted to partially affect the transcription mechanism. The present study aims to unravel the role of exogenous Trp amino acid in TRP protein for transcriptional regulatory mechanism.