Calibration of effective van der Waals atomic contact radii for proteins and peptides

Iijima, Hiroshi; Dunbar, James B.; Marshall, Garland R.

doi:10.1002/prot.340020408

Cited by 68 publications

(47 citation statements)

References 72 publications

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“…The main issue pertaining to repulsive effects is the choice of hard-sphere radii. Our radii are among the most permissive, close to the lower limits set by Ijima et al (29). Also, the N-C ␣ -CЈ bond angles are strained slightly to accommodate experimentally confirmed conformations at the edge of allowed regions (18,30).…”

Section: Discussionsupporting

confidence: 48%

The Flory isolated-pair hypothesis is not valid for polypeptide chains: Implications for protein folding

Pappu

Srinivasan

Rose³

2000

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

285

317

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Using an all-atom representation, we exhaustively enumerate all sterically allowed conformations for short polyalanyl chains. Only intrachain interactions are considered, including one adjustable parameter, a favorable backbone energy (e.g., a peptide hydrogen bond). The counting is used to reevaluate Flory's isolated-pair hypothesis, the simplifying assumption that each , pair is sterically independent. This hypothesis is a conceptual linchpin in helix-coil theories and protein folding. Contrary to the hypothesis, we find that systematic local steric effects can extend beyond nearest-chain neighbors and can restrict the size of accessible conformational space significantly. As a result, the entropy price that must be paid to adopt any specific conformation is far less than previously thought. helix-coil theory ͉ Levinthal paradoxWe will have to decide whether the assembly, when left to itself in the way already specified, tends to settle down mainly into one or other of a small preferred group of stationary states, whose properties are or control the equilibrium properties of the assembly; or whether it shows no such discrimination, but wanders apparently or effectively at random over the whole range of stationary states made accessible by the general conditions of the problem (1).T he central thermodynamic question in protein folding is: How can a polypeptide chain overcome conformational entropy and fold to its native state (2)? Typically, the unfolded state is depicted as a rugged energy landscape with an exorbitant number of local minima. Under suitable conditions, the protein negotiates this landscape spontaneously and finds its way to the global minimumthe native state.This view of the unfolded state corresponds to the latter case referred to by Fowler and Guggenheim (1), in which the assembly wanders apparently at random over the whole range of conceivable stationary states. The view was placed on a rigorous foundation by the work of Flory (3), who showed that each , pair in the peptide backbone is sterically insensitive to the values of its neighbors. Flory's simplifying conclusion is known as the isolated-pair hypothesis.The isolated-pair hypothesis has influenced the development of helix-coil (4-6) and protein-folding theories (7). It follows from the hypothesis that local structural transitions are ruled out as a possible origin of cooperativity in protein folding (8); the entropic price is simply too high for short polypeptide backbones to preferentially populate a small set of highly similar conformations.In contrast to these ideas, both experiments (9) and calculations (10) suggest the prevalence of biases in polypeptide chains, which motivated us to reevaluate the isolated-pair hypothesis. We find that the former case referred to by Fowler and Guggenheim-in which a small preferred group of states account for the equilibrium properties of the assembly-better describes the situation for polypeptide chains in both folded and unfolded forms. The validity of the isolated-pair hypothesis has also been ...

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Section: Discussionsupporting

confidence: 48%

The Flory isolated-pair hypothesis is not valid for polypeptide chains: Implications for protein folding

Pappu

Srinivasan

Rose³

2000

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

285

317

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“…Not every conformation generated in this way is feasible due to steric hindrances. For each conformation, van der Waals collitions are checked by using the set of effective van der Waals radii MMII published by Iijima et al 24 Those conformations that exhibit van der Waals collitions are rejected. The Gibbs potential function ⌬G ef is calculated only for allowed conformations.…”

Section: Side Chain Conformationsmentioning

confidence: 99%

Structure-based thermodynamic design of peptide ligands: Application to peptide inhibitors of the aspartic protease endothiapepsin

et al. 1998

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The prediction of binding affinities from structure is a necessary requirement in the development of structure-based molecular design strategies. In this paper, a structural parameterization of the energetics previously developed in this laboratory has been incorporated into a molecular design algorithm aimed at identifying peptide conformations that minimize the Gibbs energy. This approach has been employed in the design of mutants of the aspartic protease inhibitor pepstatin A. The simplest design strategy involves mutation and/or chain length modification of the wild-type peptide inhibitor. The structural parameterization allows evaluation of the contribution of different amino acids to the Gibbs energy in the wild-type structure, and therefore the identification of potential targets for mutation in the original peptide. The structure of the wild-type complex is used as a template to generate families of conformational structures in which specific residues have been mutated. The most probable conformations of the mutated peptides are identified by systematically rotating around the side-chain and backbone torsional angles and calculating the Gibbs potential function of each conformation according to the structural parametrization. The accuracy of this approach has been tested by chemically synthesizing two different mutants of pepstatin A. In one mutant, the alanine at position five has been replaced by a phenylalanine, and in the second one a glutamate has been added at the carboxy terminus of pepstatin A. The thermodynamics of association of pepstatin A and the two mutants have been measured experimentally and the results compared with the predictions. The difference between experimental and predicted Gibbs energies for pepstatin A and the two mutants is 0.23 +/- 0.06 kcal/mol. The excellent agreement between experimental and predicted values demonstrates that this approach can be used in the optimization of peptide ligands.

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“…37 Such reductions are not uncommon in hard-sphere potential models attempting to reproduce sterically allowed protein conformations. 21,38,39 Calculations were performed with a novel algorithm that combines analytical and numerical techniques to accelerate the computation of these van der Waals molecular volumes and surface areas. 31 As these effective van der Waals volumes are considerably less solvent-or conformation-dependent than, for example, solvent-accessible surfaces, simple molecular mechanics optimizations gave sufficiently reproducible values.…”

Section: Modelmentioning

confidence: 99%

Octanol–water partition of nonzwitterionic peptides: Predictive power of a molecular size-based model

Buchwald

Bodor

1998

Proteins

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A remarkably simple, molecular size-based model developed to predict octanol-water partition coefficients for organic compounds is tested on a set of 188 neutral peptides with available experimental partition data. Despite using only two parameters, it gives a promising correlation (r2 = 0.914; sigma = 0.455, F = 1978.0), and predictions are in a realistic range even for larger peptides (cyclosporin, melanotan, sandostatin) where common, overparametrized fragment methods become quite unreliable. Ion-pair partitioning and the extraction constant formalism is briefly reviewed to describe the sigmoidal lipophilicity profile of ionizable, nonzwitterionic peptides. It seems possible to extend the present model to estimate apparent partition coefficients measured around neutral pH and physiological conditions for monoionic peptides; however, as no standard conditions are yet defined and only relatively small number of experimental data are available, the situation here is more complex.

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Calibration of effective van der Waals atomic contact radii for proteins and peptides

Cited by 68 publications

References 72 publications

The Flory isolated-pair hypothesis is not valid for polypeptide chains: Implications for protein folding

The Flory isolated-pair hypothesis is not valid for polypeptide chains: Implications for protein folding

Structure-based thermodynamic design of peptide ligands: Application to peptide inhibitors of the aspartic protease endothiapepsin

Octanol–water partition of nonzwitterionic peptides: Predictive power of a molecular size-based model

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