Computer modeling of protein folding: conformational and energetic analysis of reduced and detailed protein models.

Recently we developed methods to generate low-resolution protein tertiary structures using a reduced model of the protein where secondary structure is specified and a simple potential based on a statistical analysis of the Protein Data Bank is employed. Here we present the results of an extensive analysis of a large number of detailed, all-atom structures generated from these reduced model structures. Following side-chain addition, minimization and simulated annealing simulations are carried out with a molecular mechanics potential including an approximate continuum solvent treatment. By combining reduced model simulations with molecular modeling calculations we generate energetically competitive, plausible misfolded structures which provide a more significant test of the potential function than current misfolded models based on superimposing the native sequence on the folded structures of completely different proteins. The various contributions to the total energy and their interdependence are analyzed in detail for many conformations of three proteins (myoglobin, the C-terminal fragment of the L7/L12 ribosomal protein, and the N-terminal domain of phage 434 repressor). Our analysis indicates that the all-atom potential performs reasonably well in distinguishing the native structure. It also reveals inadequacies in the reduced model potential, which suggests how this potential can be improved to yield greater accuracy. Preliminary results with an improved potential are presented.

[1]  M Levitt,et al.  Folding and stability of helical proteins: carp myogen. , 1976, Journal of molecular biology.

[2]  M. Levitt,et al.  Conformation of amino acid side-chains in proteins. , 1978, Journal of molecular biology.

[3]  M. Karplus,et al.  An analysis of incorrectly folded protein models. Implications for structure predictions. , 1984, Journal of molecular biology.

[4]  R. Sharon,et al.  Accurate simulation of protein dynamics in solution. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[5]  G. Chang,et al.  Macromodel—an integrated software system for modeling organic and bioorganic molecules using molecular mechanics , 1990 .

[6]  D. Covell,et al.  Conformations of folded proteins in restricted spaces. , 1990, Biochemistry.

[7]  W. C. Still,et al.  Semianalytical treatment of solvation for molecular mechanics and dynamics , 1990 .

[8]  Karplus,et al.  Protein folding bottlenecks: A lattice Monte Carlo simulation. , 1991, Physical review letters.

[9]  M. Levitt,et al.  A molecular dynamics simulation of the C-terminal fragment of the L7/L12 ribosomal protein in solution , 1991 .

[10]  G. Wider,et al.  Protein secondary structure determination by NMR Application with recombinant human cyclophilin , 1991, FEBS letters.

[11]  P. Wolynes,et al.  Generalized protein tertiary structure recognition using associative memory Hamiltonians. , 1991, Journal of molecular biology.

[12]  D. Covell.  Folding protein α‐carbon chains into compact forms by monte carlo methods , 1992 .

[13]  B Honig,et al.  Analysis of the heat capacity dependence of protein folding. , 1992, Journal of molecular biology.

[14]  W F van Gunsteren,et al.  Simulation of the thermal denaturation of hen egg white lysozyme: trapping the molten globule state. , 1992, Biochemistry.

[15]  F. Richards,et al.  The chemical shift index: a fast and simple method for the assignment of protein secondary structure through NMR spectroscopy. , 1992, Biochemistry.

[16]  G. Crippen,et al.  Contact potential that recognizes the correct folding of globular proteins. , 1992, Journal of molecular biology.

[17]  W. Clark Still,et al.  AMBER torsional parameters for the peptide backbone , 1992 .

[18]  Johan Desmet,et al.  The dead-end elimination theorem and its use in protein side-chain positioning , 1992, Nature.

[19]  A. Godzik,et al.  A general method for the prediction of the three dimensional structure and folding pathway of globular proteins: Application to designed helical proteins , 1993 .

[20]  S. Sun,et al.  Reduced representation model of protein structure prediction: Statistical potential and genetic algorithms , 1993, Protein science : a publication of the Protein Society.

[21]  A Kolinski,et al.  Prediction of the folding pathways and structure of the GCN4 leucine zipper. , 1994, Journal of molecular biology.

[22]  Richard A. Friesner,et al.  Hierarchical algorithm for computer modeling of protein tertiary structure: folding of myoglobin to 6.2 .ANG. resolution , 1994 .