Self-Complementarity within Proteins: Bridging the Gap between Binding and Folding

Abstract

Complementarity, in terms of both shape and electrostatic potential, has been quantitatively estimated at proteinprotein interfaces and used extensively to predict the specific geometry of association between interacting proteins. In this work, we attempted to place both binding and folding on a common conceptual platform based on complementarity. To that end, we estimated (for the first time to our knowledge) electrostatic complementarity (E m) for residues buried within proteins. E m measures the correlation of surface electrostatic potential at protein interiors. The results show fairly uniform and significant values for all amino acids. Interestingly, hydrophobic side chains also attain appreciable complementarity primarily due to the trajectory of the main chain. Previous work from our laboratory characterized the surface (or shape) complementarity (S m) of interior residues, and both of these measures have now been combined to derive two scoring functions to identify the native fold amid a set of decoys. These scoring functions are somewhat similar to functions that discriminate among multiple solutions in a protein-protein docking exercise. The performances of both of these functions on state-of-the-art databases were comparable if not better than most currently available scoring functions. Thus, analogously to interfacial residues of protein chains associated (docked) with specific geometry, amino acids found in the native interior have to satisfy fairly stringent constraints in terms of both S m and E m. The functions were also found to be useful for correctly identifying the same fold for two sequences with low sequence identity. Finally, inspired by the Ramachandran plot, we developed a plot of S m versus E m (referred to as the complementarity plot) that identifies residues with suboptimal packing and electrostatics which appear to be correlated to coordinate errors.

SARAMA: A Standalone Suite of Programs for the Complementarity Plot—A Graphical Structure Validation Tool for Proteins

“…The basic methodology has already been reported. 1 Briefly, the Complementarity Plot (CP) estimates the shape and electrostatic complementarity of interior residues of a globular protein and is a sensitive indicator of their harmony or disharmony with regard to the short and long range forces sustaining the native fold. A correctly determined natively folded protein structure should have optimal packing between its buried side-chains and absence of destabilizing unbalanced electric fields within the interior of the molecule.…”

“…For electrostatic complementarity (E sc m ), the electrostatic potential of the molecular surface was estimated using the finite difference Poisson-Boltzmann method as implemented in DelPhi. 5 The potential on the side-chain surface points of a buried residue was then computed twice, 1 first, due to all atoms of the target residue and second as a function of all atoms from the rest of the polypeptide chain (excluding the target). Thus, each surface point was tagged with two values of electrostatic potential.…”

“…The plot of S sc m on the X-axis and E sc m on the Y -axis (spanning − 1 to 1 in both axes) constitutes the 'Complementarity Plot' (CP), which is actually divided into three plots based on the burial ranges: 0 00 ≤ Bur ≤ 0 05 (CP1), 0 05 < Bur ≤ 0 15 (CP2) and 0 15 < Bur ≤ 0 30 (CP3). Initially, all the buried residues from a training database (DB2) consisting of 400 highly resolved protein crystal structures 1 were plotted in the CPs, which had been divided into square-grids (of width 0 05 × 0 05), and the center of every square grid was assigned an initial probability (P grid equal to the number of points in the grid divided by the total number of points in the plot. The probability of a residue to occupy a specific position in the plot was then estimated by bilinear interpolation from the probability values of its four nearest neighboring voxels.…”

CPdock: The Complementarity Plot for Docking of Proteins: Implementing Multi-dielectric Continuum Electrostatics

“…The Complementarity plot (CP) is an established graphical structure validation tool in the field of protein science originally proposed for globular proteins [1][2][3] and later extended for experimentally solved protein co-complexes [4]. So far, this has been constructed and applied to analyze complementarity in a residue-wise manner in proteins.…”

“…The subject has been further complicated by paradoxical observations like the presence of ionic groups in the hydrophobic protein interior without having to adapt to any specialized structures to get stabilized, demanding a considerably higher effect experienced locally at these sites than can be accounted for by the low dielectric constant traditionally assigned to represent the hydrophobic protein interior in continuum models [10]. Primarily contributed by this 'dielectric problem', electrostatic complementarity of individual amino acid residues (Em) within a folded protein chain remained undetermined, until the problem was finally adequately addressed by the same study [1] that put forward the Complementarity Plot (CP). Briefly, the study had shown that electrostatic complementarity (being a correlation function between two troughs of potential values) is independent of any single dielectric constant assigned to the protein interior, treated as the internal dielectric of the continuum [1].…”