Peptide Bond Distortions from Planarity: New Insights from Quantum Mechanical Calculations and Peptide/Protein Crystal Structures

Abstract

By combining quantum-mechanical analysis and statistical survey of peptide/protein structure databases we here report a thorough investigation of the conformational dependence of the geometry of peptide bond, the basic element of protein structures. Different peptide model systems have been studied by an integrated quantum mechanical approach, employing DFT, MP2 and CCSD(T) calculations, both in aqueous solution and in the gas phase. Also in absence of inter-residue interactions, small distortions from the planarity are more a rule than an exception, and they are mainly determined by the backbone ψ dihedral angle. These indications are fully corroborated by a statistical survey of accurate protein/peptide structures. Orbital analysis shows that orbital interactions between the σ system of Cα substituents and the π system of the amide bond are crucial for the modulation of peptide bond distortions. Our study thus indicates that, although long-range inter-molecular interactions can obviously affect the peptide planarity, their influence is statistically averaged. Therefore, the variability of peptide bond geometry in proteins is remarkably reproduced by extremely simplified systems since local factors are the main driving force of these observed trends. The implications of the present findings for protein structure determination, validation and prediction are also discussed.

Restricting the ψ Torsion Angle Has Stereoelectronic Consequences on a Scissile Bond: An Electronic Structure Analysis

“…These results are entirely consistent with the model that holds that ψ modulates both electronic (n N → π * interaction) and geometric ( χ C ) parameters. 23 From a stereoelectronic point of view, the importance of ψ could be a result of steric interactions. As ψ moves closer to 0°, the four-electron closed-shell repulsion between the filled orbitals of the vicinal NH groups could force the carbonyl and nitrogen to pyramidalize, 48 which in turn would lead to a reduction in the n N → π * interaction.…”

On the reliability of peptide nonplanarity seen in ultra‐high resolution crystal structures

“…Examples include: the geometric distortions of ligands and protein groups in enzyme active sites; 6-10 the systematic variation in peptide backbone bond angles as a function of the backbone conformation in commonly observed regions of /,wspace 11 and in rarely observed high-energy transition conformations; 12 and a level of nonplanarity of the peptide unit in proteins much greater than expected based on data from lower resolution protein crystal structures that were strongly influenced by peptide planarity restraints. 13 In the case of peptide nonplanarity, our group 13 built on the work of others 5,14,15 to show that in protein structures determined at 1 Å resolution and better, the x torsion angles (defined by the Ca i21 -C i21 -N i -Ca i atoms and equal to 1808 for a perfectly planar trans peptide unit) are rather broadly distributed. The standard deviation was 6.38 for trans peptide bonds with about 12% and 0.5% of residues deviating more than 108and 208, respectively, from planarity.…”

Contribution of the empirical dispersion correction on the conformation of short alanine peptides obtained by gas-phase QM calculations

“…5–9 Moreover, advances in computer technology have allowed researchers to perform calculations with progressively larger basis sets and higher levels of theory. 10–12 Earlier work 10,11,13–15 shows that the inclusion of electron correlation in QM calculations affects to different degrees the conformational propensity of small peptides and the stability of helical motifs. Accounting for electron correlation in an approximate fashion, less computationally expensive methods based on density functional theory (DFT) have often provided a speedy and reliable description of the conformational energy of minimal peptide models.…”