Experimentally observed conformation‐dependent geometry and hidden strain in proteins

Abstract

A database has been compiled documenting the peptide conformations and geometries from 70 diverse proteins refined at 1.75 A or better. Analysis of the well-ordered residues within the database shows 4, $-distributions that have more fine structure than is generally observed. Also, clear evidence is presented that the peptide covalent geometry depends on conformation, with the interpeptide N-Ca-C bond angle varying by nearly +-5 degrees from its standard value. The observed deviations from standard peptide geometry are greatest near the edges of wellpopulated regions, consistent with strain occurring in these conformations. Minimization of such hidden strain could be an important factor in thermostability of proteins. These empirical data describing how equilibrium peptide geometry varies as a function of conformation confirm and extend quantum mechanics calculations, and have predictive value that will aid both theoretical and experimental analyses of protein structure.Keywords: amino acids; conformational energetics; local geometry; peptide geometry; protein folding; protein stability; protein structure; Ramachandran plot In a landmark paper, Ramachandran and Sasisekharan (1968) reviewed concepts put forth originally by Sasisekharan (1962) to show how two main-chain torsion angles, and $, are the key variables for describing protein conformation, and how simple spatial exclusion considerations place major limitations on the conformations accessible to polypeptides (Fig. 1). They also outlined how more realistic analyses using van der Waals potentials convert the simple allowed/disallowed distinction to a continuous function of conformational energy. The general agreement of these plots with the observed conformations in proteins (compare Fig. lA,B) has provided strong evidence that local interactions within a single dipeptide are of primary importance to conformational preferences.However, s i~~f i~t deviations between the ( 6 , $-~stributions observed in proteins and calculated energetics have spurred much effort to determine more accurately the energetics of dipeptide conformations. These calculations have been made with various empirical force fields and quantum mechanics, with and without solvation terms, generating both "rigid-geometry" energy maps by assuming a fixed peptide geometry and "relaxedgeometry," or "local geometry," energy maps by allowing the covalent peptide geometry to be minimized at each point of the 4, $-map (reviewed in Brooks & Case, 1993). Although the -_ _ _ I _ Reprint requests to: P.

Halogen bonds in biological molecules

“…The nearly perpendicular approach of the halogen toward certain OAC oxygens in a separate group of halogen bonds can be attributed to the involvement of the electrons of the peptide bonds. Perpendicular interactions to the peptide backbone are often ignored in molecular interactions (24,25); however, the prevalence of -system donors seen in this survey shows them to be very important in halogen bonding.…”

Crystal structures of two mutants that have implications for the folding of bovine pancreatic ribonuclease A

“…Although the trans conformation appeared to fit the density reasonably well, it leads to torsion angles for Ala93 (4 = 1 13". I// = -26") that have never been observed for alanine residues in a database of highresolution protein crystal structures (Karplus, 1996). By contrast, this database contains five examples of nonproline residues that are preceded by cis peptide bonds.…”

Functional Dissection of Naturally Occurring Amino Acid Substitutions in eIF4E That Confers Recessive Potyvirus Resistance in Plants

“…In the NMR structure of yeast eIF4E, where Gly is substituted by Lys (K90), the conformation of residue K90 (f ¼ þ46, c ¼ þ25) has shifted toward the a L region of the Ramachandran plot from the highly unfavorable region occupied by G88 in mouse and human eIF4E. However, the stress in the loop region seems to be distributed among a few neighboring residues, including L89 (with f ¼ þ36, c ¼ À158) and P88 (with f ¼ À78, c ¼ þ42), that have been forced into energetically less-favorable regions of the conformational map (Karplus, 1996) and may act to relieve the stress on the loop caused by K90. In the case of the G107R substitution in eIF4E-pvr1, there is no such residue to perform a similar role.…”