Computational and experimental analysis of short peptide motifs for enzyme inhibition
| Autor: | Azka Ahmed, Junhao Dong, Jinglin Fu, Anthony Cooper, Ting Zhang, Minyoung Lee, John W. Whittaker, Luca Larini |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Proteomics
Amino Acid Motifs lcsh:Medicine Peptide 02 engineering and technology Plasma protein binding Molecular Dynamics Biochemistry 01 natural sciences Protein Structure Secondary Database and Informatics Methods Computational Chemistry Protein structure Enzyme Inhibitors Amino Acids lcsh:Science Peptide Libraries chemistry.chemical_classification Alanine Multidisciplinary Organic Compounds Chemical Synthesis Alanine scanning 021001 nanoscience & nanotechnology Enzymes 3. Good health Chemistry Physical Sciences 0210 nano-technology Sequence Analysis Protein Binding Research Article Biosynthetic Techniques Bioinformatics Library Screening Molecular Dynamics Simulation Research and Analysis Methods 010402 general chemistry Inhibitory Concentration 50 Sequence Motif Analysis Binding site Molecular Biology Techniques Molecular Biology Peptide Synthesis Molecular Biology Assays and Analysis Techniques Binding Sites lcsh:R Organic Chemistry Chemical Compounds Biology and Life Sciences Proteins beta-Galactosidase 0104 chemical sciences Enzyme Activation Enzyme Aliphatic Amino Acids chemistry Enzymology lcsh:Q Peptides Function (biology) |
| Zdroj: | PLoS ONE PLoS ONE, Vol 12, Iss 8, p e0182847 (2017) |
| ISSN: | 1932-6203 |
| Popis: | The metabolism of living systems involves many enzymes that play key roles as catalysts and are essential to biological function. Searching ligands with the ability to modulate enzyme activities is central to diagnosis and therapeutics. Peptides represent a promising class of potential enzyme modulators due to the large chemical diversity, and well-established methods for library synthesis. Peptides and their derivatives are found to play critical roles in modulating enzymes and mediating cellular uptakes, which are increasingly valuable in therapeutics. We present a methodology that uses molecular dynamics (MD) and point-variant screening to identify short peptide motifs that are critical for inhibiting β-galactosidase (β-Gal). MD was used to simulate the conformations of peptides and to suggest short motifs that were most populated in simulated conformations. The function of the simulated motifs was further validated by the experimental point-variant screening as critical segments for inhibiting the enzyme. Based on the validated motifs, we eventually identified a 7-mer short peptide for inhibiting an enzyme with low μM IC50. The advantage of our methodology is the relatively simplified simulation that is informative enough to identify the critical sequence of a peptide inhibitor, with a precision comparable to truncation and alanine scanning experiments. Our combined experimental and computational approach does not rely on a detailed understanding of mechanistic and structural details. The MD simulation suggests the populated motifs that are consistent with the results of the experimental alanine and truncation scanning. This approach appears to be applicable to both natural and artificial peptides. With more discovered short motifs in the future, they could be exploited for modulating biocatalysis, and developing new medicine. |
| Databáze: | OpenAIRE |
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