Non-randomness in side-chain packing: the distribution of interplanar angles

Mitchell, John B. O.; Laskowski, Roman A.; Thornton, Janet

doi:10.1002/(sici)1097-0134(199711)29:3<370::aid-prot10>3.0.co;2-k

Cited by 41 publications

(30 citation statements)

References 40 publications

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“…Other energetic interactions must bias sidechain conformations toward the native state, leading to the observation of directional packing in protein structures. 19 The three models employed in our study yield consistent results. All three vastly reduce the total number of available states.…”

Section: Discussionsupporting

confidence: 66%

Excluded volume in protein side-chain packing

Kussell

Shimada

Shakhnovich

2001

Journal of Molecular Biology

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The excluded volume occupied by protein sidechains and the requirement of high packing density in the protein interior should severely limit the number of sidechain conformations compatible with a given native backbone. To examine the relationship between sidechain geometry and sidechain packing, we use an all-atom Monte Carlo simulation to sample the large space of sidechain conformations. We study three models of excluded volume and use umbrella sampling to effectively explore the entire space. We find that while excluded volume constraints reduce the size of conformational space by many orders of magnitude, the number of allowed conformations is still large. An average repacked conformation has 20% of its χ angles in a non-native state, a marked reduction from the expected 67% in the absence of excluded volume. Interestingly, well-packed conformations with up to 50% non-native χ's exist. The repacked conformations have native packing density as measured by a standard Voronoi procedure. Entropy is distributed non-uniformly over positions, and we partially explain the observed distribution using rotamer probabilities derived from the pdb database. 1In several cases, native rotamers which occur infrequently in the pdb database are seen with high probability in our simulation, indicating that sequence-specific excluded volume interactions can stabilize rotamers that are rare for a given backbone. In spite of our finding that 65% of the native rotamers and 85% of χ 1 angles can be correctly predicted on the basis of excluded volume only, 95% of positions can accomodate more than 1 rotamer in simulation. We estimate that in order to quench the sidechain entropy observed in the presence of excluded volume interactions, other interactions (hydrophobic, polar, electrostatic) must provide an additional stabilization of at least 0.6 kT per residue in order to single out the native state.2

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Section: Discussionsupporting

confidence: 66%

Excluded volume in protein side-chain packing

Kussell

Shimada

Shakhnovich

2001

Journal of Molecular Biology

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“…By using a 6.0-Å distance cutoff and no other geometrical constraints, 359 potential cation-pairs were selected from a dataset of 68 nonhomologous, high-resolution protein structures (16). Each pair then was reduced to a system that could be studied computationally.…”

Section: Methodsmentioning

confidence: 99%

“…It is now appreciated that the interaction of a cationic group with an aromatic-a cation-interaction-is much more favorable than an analogous interaction involving a neutral amine (10,11). Important subsequent studies by Thornton (12)(13)(14)(15)(16)(17) modified the Burley and Petsko analysis, especially with regard to the amino-aromatic ''hydrogen bond.'' In addition, explicit studies of Arg interacting with aromatic residues have been reported by Flocco and Mowbray (18) and by Thornton (14), and other efforts to search the Protein Data Bank (PDB) for cation-interactions between ligands and proteins have been reported (19,20).…”

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confidence: 99%

Cation-π interactions in structural biology

Gallivan

Dougherty

1999

Proc. Natl. Acad. Sci. U.S.A.

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1,679

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Cation-interactions in protein structures are identified and evaluated by using an energy-based criterion for selecting significant sidechain pairs. Cation-interactions are found to be common among structures in the Protein Data Bank, and it is clearly demonstrated that, when a cationic sidechain (Lys or Arg) is near an aromatic sidechain (Phe, Tyr, or Trp), the geometry is biased toward one that would experience a favorable cation-interaction. The sidechain of Arg is more likely than that of Lys to be in a cation-interaction. Among the aromatics, a strong bias toward Trp is clear, such that over one-fourth of all tryptophans in the data bank experience an energetically significant cation-interaction.The three-dimensional structure of a protein is determined by a delicate balance of weak interactions. Hydrogen bonds, salt bridges, and the hydrophobic effect all play roles in folding a protein and establishing its final structure. In addition, the cation-interaction (1-3) is increasingly recognized as an important noncovalent binding interaction relevant to structural biology. Theoretical and experimental studies have shown that cation-interactions can be quite strong, both in the gas phase and in aqueous media. A number of studies have established a role for cation-interactions in biological recognition, especially in the binding of acetylcholine (4, 5). Here we present a detailed analysis of the extent and nature of cation-interactions that are intrinsic to a protein's structure and likely contribute to protein stability. We find that energetically significant cation-interactions are common in proteins-a ''typical'' protein will contain several. We also have documented some significant preferences for certain amino acid pairs as partners in a cation-interaction.Important early work indicated a role for cation-interactions in protein structures. Following work by Levitt and Perutz (6-8) suggesting a hydrogen bond between aromatic and amino groups, Burley and Petsko identified the ''amino aromatic'' interaction (9), in which NH-containing groups tend to be positioned near aromatic rings within proteins. It is now appreciated that the interaction of a cationic group with an aromatic-a cation-interaction-is much more favorable than an analogous interaction involving a neutral amine (10, 11). Important subsequent studies by Thornton (12-17) modified the Burley and Petsko analysis, especially with regard to the amino-aromatic ''hydrogen bond.'' In addition, explicit studies of Arg interacting with aromatic residues have been reported by Flocco and Mowbray (18) and by Thornton (14), and other efforts to search the Protein Data Bank (PDB) for cation-interactions between ligands and proteins have been reported (19,20).Previous protein database searches relied on geometric definitions of sidechain interactions, focusing on when a cationic sidechain displayed a certain distance͞angle relationship to an aromatic sidechain. The different geometries of Lys vs. Arg and Trp vs. Phe͞Tyr can make such comparisons proble...

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“…[17][18][19][20][21][22][23] Quantum chemistry and molecular mechanics calculations have identified the energy minima for pairs of interacting residues, and protein structural analysis has described the distributions of interaction geometries for different residue pairs. Previously, we used density functional theory to compute dimer energy landscapes for pairs of ring-containing amino acids, and compared these landscapes to molecular mechanics energy landscapes.…”

Section: Introductionmentioning

confidence: 99%