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Structure-Based Prediction of Potential Binding and Nonbinding Peptides to HIV-1 Protease
- Source :
- Biophysical Journal. 85(2):853-863
- Publication Year :
- 2003
- Publisher :
- Elsevier BV, 2003.
-
Abstract
- HIV-1 protease is a major drug target against AIDS as it permits viral maturation by processing the gag and pol polyproteins of the virus. The cleavage sites in these polyproteins do not have obvious sequence homology or a binding motif and the specificity of the protease is not easily determined. We used various threading approaches, together with the crystal structures of substrate complexes which served as template structures, to study the substrate specificity of HIV-1 protease with the aim of obtaining a better differentiation between binding and nonbinding sequences. The predictions from threading improved when distance-dependent interaction energy functions were used instead of contact matrices. To rank the peptides and properly account for the peptide's conformation in the total energy, the results from using short-range potentials on multiple template structures were averaged. Finally, a dynamic threading approach is introduced which is potentially useful for cases when there is only one template structure available. The conformational energy of the peptide—especially the term accounting for the side chains—was found to be important in differentiating between binding and nonbinding sequences. Hence, the substrate specificity, and thus the ability of the virus to mature, is affected by the compatibility of the substrate peptide to fit within the limited conformational space of the active site groove.
- Subjects :
- Models, Molecular
Polyproteins
Macromolecular Substances
medicine.medical_treatment
Biophysics
Gene Products, gag
Gene Products, pol
Peptide
Plasma protein binding
Biophysical Theory and Modeling
Substrate Specificity
Motion
Structure-Activity Relationship
HIV-1 protease
HIV Protease
Enzyme Stability
medicine
Electrochemistry
Computer Simulation
Binding site
chemistry.chemical_classification
Protease
Binding Sites
biology
Active site
Enzyme Activation
Biochemistry
chemistry
Energy Transfer
Models, Chemical
biology.protein
Threading (protein sequence)
Protein Binding
Subjects
Details
- ISSN :
- 00063495
- Volume :
- 85
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Biophysical Journal
- Accession number :
- edsair.doi.dedup.....20567d99ce143756bd95b73653d3d756
- Full Text :
- https://doi.org/10.1016/s0006-3495(03)74525-1