Local Geometry Trends and Torsional Sensitivity in N-Formyl-l-alanyl-l-alanine Amide and the Limitations of the Dipeptide Approximation

Abstract

Based on a database of 11 664 RHF/4-21G ab initio gradient-optimized structures of N-formyl-l-alanyl-l-alanine amide (ALA-ALA), the local geometries and torsional sensitivity of this compound were analyzed to test the dipeptide approximation frequently used in peptide conformational analyses. This database was generated by optimizing the geometries of this compound at grid points in its four-dimensional (φ1,ψ1,φ2,ψ2) conformational space defined by 40° increments along the outer torsions φ1 and ψ2, and by 30° increments along the inner torsions ψ1 and φ2. Using cubic spline functions, the grid structures were then used to construct analytical representations of complete surfaces of the structural parameters of ALA-ALA, and of their gradients, in (φ1,ψ1,φ2,ψ2) space. Analysis of the structural surfaces shows not only that the structure of a given residue in a peptide chain depends acutely on the conformational state of a neighboring residue but also that the interresidue effects differ, depending on whether they are transmitted from right to left or from left to right in the peptide chain. Structural gradients are a qualitative measure of the torsional sensitivity, and therefore of the density of states and contributions to vibrational entropy. Analyses of the gradient surfaces show that the density of states in a residue is significantly affected by the dynamics of a neighboring residue. This opens the possibility of dynamic entropic conformational steering in extended peptide chains, i.e., the generation of free energy contributions from dynamic effects of one part of a molecule on another, possibly stabilizing a conformational region of a PES whose static energy profile is less favorable compared to other regions. The gradient trends illustrate how the overall stability of a complex molecule is not only a function of how the static energy minima of its isolated subunits combine but also of how the dynamics of the subunits interact with one other. These interactions between individual residues represent a hidden cooperative effect that is not apparent at all in the dynamics of isolated dipeptide units.

Intrinsically Stable Secondary Structure Elements of Proteins: A Comprehensive Study of Folding Units of Proteins by Computation and by Analysis of Data Determined by X‐ray Crystallography

“…For labeling schemes and structural data, see refs. 33–36, in which selected turn conformers of diamino acid dipeptides were previously computed and analyzed.…”

The SAAP force field. A simple approach to a new all‐atom protein force field by using single amino acid potential (SAAP) functions in various solvents*

“…The third term (E OTHERS ) represents a miscellaneous term, which may involve the mixed terms among the E SAAP and E INTER terms. The E OTHERS term should be less important for the total energy function than the other two terms, although significant influence of the correlation term between neighboring amino acid residues has been pointed out by Yu et al 45 Because mathematical description of the complex E OTHERS term is beyond our aims at present, it is tentatively ignored (or considered to be constant) in a current version of the SAAP force field.…”

Relative Stability of Major Types of β‐Turns as a Function of Amino Acid Composition: A Study Based on Ab Initio Energetic and Natural Abundance Data

“…β ‐turns) by means of molecular mechanic (MM) and semiempirical techniques 21. Since the early nineties more and more ab initio studies on turns have been published 22–27. In one of the first ab initio studies of β ‐turns ‐Gly‐Gly‐22 and ‐Ala‐Ala‐23 model sequences were computed at the 321G RHF level of theory.…”