Conformational analysis of thiopeptides: derivation of sp² sulfur parameters for the CFF91 force field

Abstract

When a sulfur atom is used to substitute for the oxygen in peptide bonds, its bulkiness should restrict the conformational space available to an amino acid. This conformational restriction as well as the ability to confer resistance to enzymatic degradation in the body means that thio-substituted amino acids are potentially useful building blocks for drug design. To simulate the effects of thio substitution, force field parameters for sp 2 sulfur are required. In this article, parameters for the thioamide group have been derived for the molecular mechanics CFF91 force field (available at http://www.ludwig.edu.au/archive/tran). The bond increment charges were obtained by fitting to ab initio charges and dipoles. The van der Waals parameters were obtained by fitting to high-resolution crystallographic data, and the nonbonded parameters were verified by comparing with experimentally derived lattice energy. The bonded parameters were derived by least-square fits to the ab initio calculated energy surfaces, i.e., conformational energy as well as their first and second derivatives of seven model thioamide molecules. When the sp 2 sulfur parameters were tested on a set of seven X-ray crystallographic structures from the Cambridge Structural Database, they satisfactorily reproduced the bond lengths, bond angles, torsional angles, and nonbonded distances of all the crystal structures.

Synthesis, X‐ray crystallographic structures of thio substituted N‐acetyl N′‐methylamide alanine and evaluation of sp2 sulfur parameters of the CFF91 force field

“…The X‐ray diffraction structures of both Ac‐Alat‐NHMe and Act‐Ala‐NHMe adopt β‐sheet conformation and exhibit similar hydrogen bonding patterns in which one molecular face is involved in two oxo hydrogen bonds and the molecular face is involved in two thio hydrogen bonds. The validity of our newly derived thioamide parameters (26) for the CFF91 force field was confirmed by three distinct assessments, all of which showed low deviation between the conformations obtained from X‐ray diffraction and the conformations obtained from theoretical calculations using the thioamide parameters.…”

“…The crystal structures for both Ac‐Alat‐NHMe and Act‐Ala‐NHMe provided an excellent opportunity for validating our recently derived CFF91 force field thioamide parameters (26,27) by comparing the calculated and the observed (φ, ψ) dihedral angles.…”

“… (φ, ψ) conformational energy maps for (A) Act‐Ala‐NHMe and (B) Ac‐Ala‐NHMe obtained by energy minimization with torsion forcing at every 10° increment of φ and ψ dihedral angles. Calculations were performed using the parameters from the CFF91 force field and the sp 2 sulfur parameters derived as described in the previous study in this series (26). The maps are colored white in low‐energy regions and black in high‐energy regions.…”

“…In the previous studies in this series (26,27), we derived sp 2 sulfur parameters for the CFF91 force field (28–30) and predicted that the thio substitution would restrict the conformational space available to the dipeptides as well as alter both the intramolecular and intermolecular hydrogen bonds. While the seven thio‐containing crystal structures for dithiomalonodiamide (31), thioacetamide (32), Boc‐Alat‐NHCH 3 (13) (Z)‐Glyt‐Gly‐OBzl (33), Boc‐Gly‐Alat‐Aib‐OMe (34), Boc‐Glyt‐Ala‐Aib‐OMe (34) and (Z)‐Glyt‐Glyt‐Gly‐OBzl (35) were used to evaluate the parameters and the accuracy of the calculated empirical conformational energy, they were nonideal candidates because all the molecules were end‐protected by bulky groups or contained the Aib residue, and therefore may have biased the conformation of an individual residue away from its global minimum in a dipeptide or peptide environment.…”

Effects of Thioamide Substitutions on the Conformation and Stability of α- and 310-Helices

“…Noncoding amino acids have also been used to restrict the conformational space of peptides, − allowing more predictable peptide conformers to be constructed with potential increase in binding affinity. , Furthermore, noncoding amino acids have been used to confer resistance to enzymatic degradation within the body, − to probe protein structures, − in de novo design of protein, ,− to design structures with novel fold or secondary structure, , and to create new combinatorial chemistry libraries. − When the oxygen of the peptide unit is replaced by a sp 2 sulfur atom, the thiopeptide formed becomes resistant to enzymatic degradation. , Thiopeptides have been used in structure activity relationship studies to alter biological activities, ,− and, in particular, a thio-enkephalin has been shown to have enhanced potency and a change in selectivity in both biological and binding assays . Our previous X-ray studies and conformational energy and free energy calculations of thio substituted dipeptides − suggest they are more conformationally restricted than peptides and have distinctly different hydrogen bonding properties.…”