• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of prosciprotein sciencecshl presssubscriptionsetoc alertsthe protein societyjournal home
Protein Sci. Mar 1997; 6(3): 676–688.
PMCID: PMC2143667

Derivation and testing of pair potentials for protein folding. When is the quasichemical approximation correct?


Many existing derivations of knowledge-based statistical pair potentials invoke the quasichemical approximation to estimate the expected side-chain contact frequency if there were no amino acid pair-specific interactions. At first glance, the quasichemical approximation that treats the residues in a protein as being disconnected and expresses the side-chain contact probability as being proportional to the product of the mole fractions of the pair of residues would appear to be rather severe. To investigate the validity of this approximation, we introduce two new reference states in which no specific pair interactions between amino acids are allowed, but in which the connectivity of the protein chain is retained. The first estimates the expected number of side-chain contracts by treating the protein as a Gaussian random coil polymer. The second, more realistic reference state includes the effects of chain connectivity, secondary structure, and chain compactness by estimating the expected side-chain contrast probability by placing the sequence of interest in each member of a library of structures of comparable compactness to the native conformation. The side-chain contact maps are not allowed to readjust to the sequence of interest, i.e., the side chains cannot repack. This situation would hold rigorously if all amino acids were the same size. Both reference states effectively permit the factorization of the side-chain contact probability into sequence-dependent and structure-dependent terms. Then, because the sequence distribution of amino acids in proteins is random, the quasichemical approximation to each of these reference states is shown to be excellent. Thus, the range of validity of the quasichemical approximation is determined by the magnitude of the side-chain repacking term, which is, at present, unknown. Finally, the performance of these two sets of pair interaction potentials as well as side-chain contact fraction-based interaction scales is assessed by inverse folding tests both without and with allowing for gaps.

Full Text

The Full Text of this article is available as a PDF (1.2M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Bryant SH, Lawrence CE. The frequency of ion-pair substructures in proteins is quantitatively related to electrostatic potential: a statistical model for nonbonded interactions. Proteins. 1991;9(2):108–119. [PubMed]
  • Finkelstein AV, Badretdinov AYa, Gutin AM. Why do protein architectures have Boltzmann-like statistics? Proteins. 1995 Oct;23(2):142–150. [PubMed]
  • Godzik A. Knowledge-based potentials for protein folding: what can we learn from known protein structures? Structure. 1996 Apr 15;4(4):363–366. [PubMed]
  • Godzik A, Kolinski A, Skolnick J. Topology fingerprint approach to the inverse protein folding problem. J Mol Biol. 1992 Sep 5;227(1):227–238. [PubMed]
  • Jernigan RL, Bahar I. Structure-derived potentials and protein simulations. Curr Opin Struct Biol. 1996 Apr;6(2):195–209. [PubMed]
  • Kolinski A, Galazka W, Skolnick J. On the origin of the cooperativity of protein folding: implications from model simulations. Proteins. 1996 Nov;26(3):271–287. [PubMed]
  • Lumb KJ, Kim PS. Measurement of interhelical electrostatic interactions in the GCN4 leucine zipper. Science. 1995 Apr 21;268(5209):436–439. [PubMed]
  • Lumb KJ, Kim PS. A buried polar interaction imparts structural uniqueness in a designed heterodimeric coiled coil. Biochemistry. 1995 Jul 11;34(27):8642–8648. [PubMed]
  • Lumb KJ, Kim PS. Response: how much solar radiation do clouds absorb? Science. 1996 Feb 23;271(5252):1137–1138. [PubMed]
  • Maiorov VN, Crippen GM. Contact potential that recognizes the correct folding of globular proteins. J Mol Biol. 1992 Oct 5;227(3):876–888. [PubMed]
  • Miyazawa S, Jernigan RL. Residue-residue potentials with a favorable contact pair term and an unfavorable high packing density term, for simulation and threading. J Mol Biol. 1996 Mar 1;256(3):623–644. [PubMed]
  • Olszewski KA, Kolinski A, Skolnick J. Folding simulations and computer redesign of protein A three-helix bundle motifs. Proteins. 1996 Jul;25(3):286–299. [PubMed]
  • Park B, Levitt M. Energy functions that discriminate X-ray and near native folds from well-constructed decoys. J Mol Biol. 1996 May 3;258(2):367–392. [PubMed]
  • Sun S. Reduced representation model of protein structure prediction: statistical potential and genetic algorithms. Protein Sci. 1993 May;2(5):762–785. [PMC free article] [PubMed]
  • Tanaka S, Scheraga HA. Medium- and long-range interaction parameters between amino acids for predicting three-dimensional structures of proteins. Macromolecules. 1976 Nov-Dec;9(6):945–950. [PubMed]

Articles from Protein Science : A Publication of the Protein Society are provided here courtesy of The Protein Society


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...