No abstract

A method is presented for the rigorous computation of the electric potential of molecules of arbitrary shape, under the assumption of continuous linear dielectric media. The computational technique involves finding the distribution of indued polarization charge on the molecular surface, and proceeds by an application of the method of boundary elements. The surface, which separates the molecular interior (of low dielectric constant) from the highly polar solvent, is given a piece-wise analytic representation as a collection of curvilinear elements. Given a set of internal fixed charges, the distribution of polarizationcharge is found as a continuous function over the surface elements, and the electric potential (including all polarization effects) is then easily computed at any point. The method is applied to a spherical interface, and to several small molecules of biological interest, including a hexapeptide. The resulting potentials show good convergence in all cases. The future application of the method to macromolecules is discussed.

This paper demonstrates the existence of regions in eight small globular proteins in which the side chains of sulfur‐containing amino acids (cysteine and methionine) alternate in space with side chains of aromatic amino acids (histidine, phenylalanine, tryptophan and tyrosine). The proteins are: rubredoxin, high potential iron protein, cytochrome c, flavodoxin, deoxyhemoglobin, trypsin inhibitor, ribonuclease‐S, and lysozyme. The sulfur‐φ‐bonded ‘chains’ involve a minimum of five and a maximum of 10 amino acids, and contain the most polarizable atoms within proteins. S‐φ‐chains give extra stability to the folding of proteins; they may also afford paths for the step‐wise movement of electrons.

We have uncovered new evidence for a significant interaction between divalent sulfur atoms and aromatic rings. Our study involves a statistical analysis of interatomic distances and other geometric descriptors derived from entries in the Cambridge Crystallographic Database (F. H. Allen and O. Kennard, Chem. Design Auto. News, 1993, Vol. 8, pp. 1 and 31–37). A set of descriptors was defined sufficient in number and type so as to elucidate completely the preferred geometry of interaction between six‐membered aromatic carbon rings and divalent sulfurs for all crystal structures of nonmetal‐bearing organic compounds present in the database. In order to test statistical significance, analogous probability distributions for the interaction of the moiety X–CH2–X with aromatic rings were computed, and taken a priori to correspond to the null hypothesis of no significant interaction. Tests of significance were carried our pairwise between probability distributions of sulfur–aromatic interaction descriptors and their CH2–aromatic analogues using the Smirnov–Kolmogorov nonparametric test (W. W. Daniel, Applied Nonparametric Statistics, Houghton‐Mifflin: Boston, New York, 1978, pp. 276–286), and in all cases significance at the 99% confidence level or better was observed. Local maxima of the probability distributions were used to define a preferred geometry of interaction between the divalent sulfur moiety and the aromatic ring. Molecular mechanics studies were performed in an effort to better understand the physical basis of the interaction. This study confirms observations based on statistics of interaction of amino acids in protein crystal structures (R. S. Morgan, C. E. Tatsch, R. H. Gushard, J. M. McAdon, and P. K. Warme, International Journal of Peptide Protein Research, 1978, Vol. 11, pp. 209–217; R. S. Morgan and J. M. McAdon, International Journal of Peptide Protein Research, 1980, Vol. 15, pp. 177–180; K. S. C. Reid, P. F. Lindley, and J. M. Thornton, FEBS Letters, 1985, Vol. 190, pp. 209–213), as well as studies involving molecular mechanics (G. Nemethy and H. A. Scheraga, Biochemistry and Biophysics Research Communications, 1981, Vol. 98, pp. 482–487) and quantum chemical calculations (B. V. Cheney, M. W. Schulz, and J. Cheney, Biochimica Biophysica Acta, 1989, Vol. 996, pp.116–124; J. Pranata, Bioorganic Chemistry, 1997, Vol. 25, pp. 213–219)—all of which point to the possible importance of the sulfur–aromatic interaction. However, the preferred geometry of the interaction, as determined from our analysis of the small‐molecule crystal data, differs significantly from that found by other approaches. © 2000 John Wiley & Sons, Inc. Biopoly 53: 233–248, 2000

A new method is presented for defining a smooth, triangulated analytic surface for biological molecules. The surface produced by the algorithm is well-suited for use with a recently developed polarizationcharge technique' for the computation of the electrostatic potential of solvated molecules, and may also be used for calculations of molecular surface areas and volumes. The new method employs Connolly's definitions of contact, reentrant and saddle surface,' but includes modifications that preclude the presence of self-interesting reentrant surface, and also insure a rigorous decomposition of contact regions into curvilinear finite elements. The triangulation algorithm may be used in conjunction with the electrostatic methods described previously to compute the electric potential of molecules of arbitrary shape in solution. Applications include the estimation of hydration enthalpies, computation of the electrostatic forces associated with solvation, estimation of interactions between separate charged species in solution, and computation of the three-dimensional form of the molecular electric potential. Test calculations are presented for a double-stranded dinucleotide, the polypeptide enkephalin, and the protein ferredoxin.