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Cavities and atomic packing in protein structures and interfaces.

ABSTRACT: A comparative analysis of cavities enclosed in a tertiary structure of proteins and interfaces formed by the interaction of two protein subunits in obligate and non-obligate categories (represented by homodimeric molecules and heterocomplexes, respectively) is presented. The total volume of cavities increases with the size of the protein (or the interface), though the exact relationship may vary in different cases. Likewise, for individual cavities also there is quantitative dependence of the volume on the number of atoms (or residues) lining the cavity. The larger cavities tend to be less spherical, solvated, and the interfaces are enriched in these. On average 15 A(3) of cavity volume is found to accommodate single water, with another 40-45 A(3) needed for each additional solvent molecule. Polar atoms/residues have a higher propensity to line solvated cavities. Relative to the frequency of occurrence in the whole structure (or interface), residues in beta-strands are found more often lining the cavities, and those in turn and loop the least. Any depression in one chain not complemented by a protrusion in the other results in a cavity in the protein-protein interface. Through the use of the Voronoi volume, the packing of residues involved in protein-protein interaction has been compared to that in the protein interior. For a comparable number of atoms the interface has about twice the number of cavities relative to the tertiary structure.

SUBMITTER: Sonavane S

PROVIDER: S-EPMC2582456 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Cavities and atomic packing in protein structures and interfaces.

Sonavane Shrihari S Chakrabarti Pinak P

PLoS computational biology 20080926 9

A comparative analysis of cavities enclosed in a tertiary structure of proteins and interfaces formed by the interaction of two protein subunits in obligate and non-obligate categories (represented by homodimeric molecules and heterocomplexes, respectively) is presented. The total volume of cavities increases with the size of the protein (or the interface), though the exact relationship may vary in different cases. Likewise, for individual cavities also there is quantitative dependence of the vo ...[more]

PMID: 19005575

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Project description:Standard volumes for atoms in double-stranded B-DNA are derived using high resolution crystal structures from the Nucleic Acid Database (NDB) and compared with corresponding values derived from crystal structures of small organic compounds in the Cambridge Structural Database (CSD). Two different methods are used to compute these volumes: the classical Voronoi method, which does not depend on the size of atoms, and the related Radical Planes method which does. Results show that atomic groups buried in the interior of double-stranded DNA are, on average, more tightly packed than in related small molecules in the CSD. The packing efficiency of DNA atoms at the interfaces of 25 high resolution protein-DNA complexes is determined by computing the ratios between the volumes of interfacial DNA atoms and the corresponding standard volumes. These ratios are found to be close to unity, indicating that the DNA atoms at protein-DNA interfaces are as closely packed as in crystals of B-DNA. Analogous volume ratios, computed for buried protein atoms, are also near unity, confirming our earlier conclusions that the packing efficiency of these atoms is similar to that in the protein interior. In addition, we examine the number, volume and solvent occupation of cavities located at the protein-DNA interfaces and compared them with those in the protein interior. Cavities are found to be ubiquitous in the interfaces as well as inside the protein moieties. The frequency of solvent occupation of cavities is however higher in the interfaces, indicating that those are more hydrated than protein interiors. Lastly, we compare our results with those obtained using two different measures of shape complementarity of the analysed interfaces, and find that the correlation between our volume ratios and these measures, as well as between the measures themselves, is weak. Our results indicate that a tightly packed environment made up of DNA, protein and solvent atoms plays a significant role in protein-DNA recognition.

Project description:BACKGROUND: In the last decade, the inhibition of protein-protein interactions (PPIs) has emerged from both academic and private research as a new way to modulate the activity of proteins. Inhibitors of these original interactions are certainly the next generation of highly innovative drugs that will reach the market in the next decade. However, in silico design of such compounds still remains challenging. METHODOLOGY/PRINCIPAL FINDINGS: Here we describe this particular PPI chemical space through the presentation of 2P2I(DB), a hand-curated database dedicated to the structure of PPIs with known inhibitors. We have analyzed protein/protein and protein/inhibitor interfaces in terms of geometrical parameters, atom and residue properties, buried accessible surface area and other biophysical parameters. The interfaces found in 2P2I(DB) were then compared to those of representative datasets of heterodimeric complexes. We propose a new classification of PPIs with known inhibitors into two classes depending on the number of segments present at the interface and corresponding to either a single secondary structure element or to a more globular interacting domain. 2P2I(DB) complexes share global shape properties with standard transient heterodimer complexes, but their accessible surface areas are significantly smaller. No major conformational changes are seen between the different states of the proteins. The interfaces are more hydrophobic than general PPI's interfaces, with less charged residues and more non-polar atoms. Finally, fifty percent of the complexes in the 2P2I(DB) dataset possess more hydrogen bonds than typical protein-protein complexes. Potential areas of study for the future are proposed, which include a new classification system consisting of specific families and the identification of PPI targets with high druggability potential based on key descriptors of the interaction. CONCLUSIONS: 2P2I database stores structural information about PPIs with known inhibitors and provides a useful tool for biologists to assess the potential druggability of their interfaces. The database can be accessed at http://2p2idb.cnrs-mrs.fr.

Dataset Information

Cavities and atomic packing in protein structures and interfaces.

Publications

Cavities and atomic packing in protein structures and interfaces.

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