Hot spots and transient pockets: predicting the determinants of small-molecule binding to a protein-protein interface.
J Chem Inf Model
; 52(1): 120-33, 2012 Jan 23.
Article
en En
| MEDLINE
| ID: mdl-22087639
Protein-protein interfaces are considered difficult targets for small-molecule protein-protein interaction modulators (PPIMs ). Here, we present for the first time a computational strategy that simultaneously considers aspects of energetics and plasticity in the context of PPIM binding to a protein interface. The strategy aims at identifying the determinants of small-molecule binding, hot spots, and transient pockets, in a protein-protein interface in order to make use of this knowledge for predicting binding modes of and ranking PPIMs with respect to their affinity. When applied to interleukin-2 (IL-2), the computationally inexpensive constrained geometric simulation method FRODA outperforms molecular dynamics simulations in sampling hydrophobic transient pockets. We introduce the PPIAnalyzer approach for identifying transient pockets on the basis of geometrical criteria only. A sequence of docking to identified transient pockets, starting structure selection based on hot spot information, RMSD clustering and intermolecular docking energies, and MM-PBSA calculations allows one to enrich IL-2 PPIMs from a set of decoys and to discriminate between subgroups of IL-2 PPIMs with low and high affinity. Our strategy will be applicable in a prospective manner where nothing else than a protein-protein complex structure is known; hence, it can well be the first step in a structure-based endeavor to identify PPIMs.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Programas Informáticos
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Receptores de Interleucina-2
/
Interleucina-2
/
Bibliotecas de Moléculas Pequeñas
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Idioma:
En
Revista:
J Chem Inf Model
Asunto de la revista:
INFORMATICA MEDICA
/
QUIMICA
Año:
2012
Tipo del documento:
Article
País de afiliación:
Alemania
Pais de publicación:
Estados Unidos