Role of electrostatic screening in determining protein main chain conformational preferences.

Amino acids display significant variation in propensity for the alpha R-helical, beta-sheet, and other main chain conformational states in proteins and peptides. The physical reason for these preferences remains controversial. Conformational entropy, steric factors, and the hydrophobic effect have all been advanced as the dominant underlying cause. In this work, we explore the role of a fourth factor, electrostatics, in determining the main chain conformation in protein molecules. Potentials of mean force derived from experimental protein structures are used to evaluate the free energy of electrostatic and other interactions of a residue in a protein environment. The local and nonlocal electrostatic interactions of main chain polar atoms are found to be crucial for determining the preferences of residues for the alpha R-helical state and other main chain conformational states of a residue. Further, the strength of local and nonlocal electrostatic interactions is shown to depend on the electrostatic screening by solvent and protein groups. Residue specific modulation of this screening in a manner related to side chain bulk and squatness produces a model that fits the observed distribution of residue conformations in proteins and recent experimental mutagenesis data on protein stability better than any other single factor.

[1]  P. Flory,et al.  The Role of Dipole Interactions in Determining Polypeptide Configurations , 1965 .

[2]  A. Warshel,et al.  Calculations of electrostatic interactions in biological systems and in solutions , 1984, Quarterly Reviews of Biophysics.

[3]  N R Kallenbach,et al.  Side chain contributions to the stability of alpha-helical structure in peptides. , 1990, Science.

[4]  James G. Boyd,et al.  The helical s constant for alanine in water derived from template-nucleated helices , 1991, Nature.

[5]  Robert L. Baldwin,et al.  Relative helix-forming tendencies of nonpolar amino acids , 1990, Nature.

[6]  C. Chothia.  Structural invariants in protein folding , 1975, Nature.

[7]  P. S. Kim,et al.  Measurement of the β-sheet-forming propensities of amino acids , 1994, Nature.

[8]  Charles L. Brooks,et al.  Theoretical study of blocked glycine and alanine peptide analogs , 1991 .

[9]  E. Stellwagen,et al.  Effect of central-residue replacements on the helical stability of a monomeric peptide. , 1990, Biochemistry.

[10]  G. Rose,et al.  Side-chain entropy opposes alpha-helix formation but rationalizes experimentally determined helix-forming propensities. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[11]  D. Chandler,et al.  Theory of the hydrophobic effect , 1977 .

[12]  Differential helix propensity of small apolar side chains studied by molecular dynamics simulations. , 1992, Biochemistry.

[13]  G J Williams,et al.  The Protein Data Bank: a computer-based archival file for macromolecular structures. , 1977, Journal of molecular biology.

[14]  F. Avbelj,et al.  Use of a potential of mean force to analyze free energy contributions in protein folding. , 1992, Biochemistry.

[15]  G M Crippen,et al.  A 1.8 Å resolution potential function for protein folding , 1990, Biopolymers.

[16]  Alan R. Fersht,et al.  Capping and α-helix stability , 1989, Nature.

[17]  Bernard Pettitt,et al.  Chloride ion pairs in water , 1987 .

[18]  J. Garnier,et al.  Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins. , 1978, Journal of molecular biology.

[19]  R. L. Baldwin,et al.  Straight-chain non-polar amino acids are good helix-formers in water. , 1991, Journal of molecular biology.

[20]  R. Jernigan,et al.  Estimation of effective interresidue contact energies from protein crystal structures: quasi-chemical approximation , 1985 .

[21]  Alan R. Fersht,et al.  Stabilization of protein structure by interaction of α-helix dipole with a charged side chain , 1988, Nature.

[22]  A. Fersht,et al.  Alpha-helix stability in proteins. II. Factors that influence stability at an internal position. , 1992, Journal of molecular biology.

[23]  Jeremy M. Berg,et al.  Thermodynamic β -sheet propensities measured using a zinc-finger host peptide , 1993, Nature.

[24]  B. Matthews,et al.  Structural basis of amino acid alpha helix propensity. , 1993, Science.

[25]  M. Sippl.  Calculation of conformational ensembles from potentials of mean force. An approach to the knowledge-based prediction of local structures in globular proteins. , 1990, Journal of molecular biology.

[26]  A. Warshel,et al.  Calculations of electrostatic energies in proteins. The energetics of ionized groups in bovine pancreatic trypsin inhibitor. , 1985, Journal of molecular biology.

[27]  B. Lee,et al.  The interpretation of protein structures: estimation of static accessibility. , 1971, Journal of molecular biology.

[28]  D. Nguyen,et al.  On achieving better than 1-A accuracy in a simulation of a large protein: Streptomyces griseus protease A. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[29]  H. Scheraga,et al.  Conformational constraints of amino acid side chains in α‐helices , 1987 .

[30]  M. Sternberg,et al.  Analysis of the relationship between side-chain conformation and secondary structure in globular proteins. , 1987, Journal of molecular biology.

[31]  Wim G. J. Hol,et al.  The role of the α-helix dipole in protein function and structure , 1985 .

[32]  Jan Hermans,et al.  Conformation equilibria of valine studies by dynamics simulation , 1991 .

[33]  B. Zimm,et al.  Theory of the Phase Transition between Helix and Random Coil in Polypeptide Chains , 1959 .

[34]  W. DeGrado,et al.  A thermodynamic scale for the helix-forming tendencies of the commonly occurring amino acids. , 1990, Science.

[35]  B. Montgomery Pettitt,et al.  Alkali halides in water: Ion–solvent correlations and ion–ion potentials of mean force at infinite dilution , 1986 .

[36]  R. H. Yun,et al.  Proline in α‐helix: Stability and conformation studied by dynamics simulation , 1991 .

[37]  P. Y. Chou,et al.  Conformational parameters for amino acids in helical, beta-sheet, and random coil regions calculated from proteins. , 1974, Biochemistry.