Makale detayı · 2023
Kinetic Barrier to Enzyme Inhibition Is Manipulated by Dynamical Local Interactions in E. coli DHFR
- Yıl
- 2023
- Tür
- article
Veri kaynağı ayrımı
- YÖKSİS YÖKSİS makale kaydı
- YÖKSİS dergi adı JOURNAL OF CHEMICAL INFORMATION AND MODELING
- Katalog eşleşmesi (ISSN) Journal of Chemical Information and Modeling
- OpenAlex OpenAlex zenginleştirmesi (özet, atıf, konular)
Özet
OpenAlex · İngilizce
Dihydrofolate reductase (DHFR) is an important drug target and a highly studied model protein for understanding enzyme dynamics. DHFR's crucial role in folate synthesis renders it an ideal candidate to understand protein function and protein evolution mechanisms. In this study, to understand how a newly proposed DHFR inhibitor, 4'-deoxy methyl trimethoprim (4'-DTMP), alters evolutionary trajectories, we studied interactions that lead to its superior performance over that of trimethoprim (TMP). To elucidate the inhibition mechanism of 4'-DTMP, we first confirmed, both computationally and experimentally, that the relative binding free energy cost for the mutation of TMP and 4'-DTMP is the same, pointing the origin of the characteristic differences to be kinetic rather than thermodynamic. We then employed an interaction-based analysis by focusing first on the active site and then on the whole enzyme. We confirmed that the polar modification in 4'-DTMP induces additional local interactions with the enzyme, particularly, the M20 loop. These changes are propagated to the whole enzyme as shifts in the hydrogen bond networks. To shed light on the allosteric interactions, we support our analysis with network-based community analysis and show that segmentation of the loop domain of inhibitor-bound DHFR must be avoided by a successful inhibitor.
Konular
Atıflar
OpenAlex cited_by_count. WoS veya Scopus atıf sayısı değildir; o kaynaklar için ayrı kolon yoktur.
11 atıf
OpenAlex cited_by_count (önbellek / veritabanı)
Yerel katalogda bu makaleye atıf yapan 11 yayın (OpenAlex referans eşleşmesi; tam dünya listesi değildir).
- Allosteric modulation of fluorescence revealed by hydrogen bond dynamics in a genetically encoded maltose biosensor 2024
- High Throughput Mutational Scanning of a Protein via Alchemistry on a High-Performance Computing Resource 2025
- High Throughput Mutational Scanning of a Protein via Alchemistry on a High‐Performance Computing Resource 2025
- Ranking Single Fluorescent Protein-Based Calcium Biosensor Performance by Molecular Dynamics Simulations 2024
- A Thermodynamic Cycle to Predict the Competitive Inhibition Outcomes of an Evolving Enzyme 2025
- A Thermodynamic Cycle to Predict the Competitive Inhibition Outcomes of an Evolving Enzyme 2025
- Allosteric Modulation of Fluorescence Revealed by Hydrogen Bond Dynamics in a Genetically Encoded Maltose Biosensor 2023
- Temporal Hydrogen-Bond Network Analysis Reveals Substrate-Directed Connectivity in Dihydrofolate Reductase 2026
- A thermodynamic cycle to predict the competitive inhibition outcomes of an evolving enzyme 2025
- Ranking Single Fluorescent Protein Based Calcium Biosensor Performance by Molecular Dynamics Simulations 2024