Circular Dichroism and Conformational Dynamics of Cephams and Their Carba and Oxa Analogues

Abstract

The biological activity of bicyclic beta-lactam antibiotics depends strongly on the absolute configuration of the bridgehead carbon atom. Frelek and co-workers proposed an empirical helicity rule relating the configuration of the bridgehead carbon atom to the sign of the 220 nm band in the electronic circular dichroism (CD) spectrum of beta-lactams. Here we use synthetic organic chemistry, CD spectroscopy, and time-dependent density functional theory (TDDFT) to investigate the validity of this structure-property relationship for eight model compounds. For conformationally flexible beta-lactams, substantial thermal effects are found which must be included in calculations. To this end, we combine TDDFT calculations of CD with full quantum-mechanical Born-Oppenheimer molecular dynamics (MD) simulations for the first time. The CD spectra are sampled with ground-state density functional trajectories of up to 60 ps. The MD simulations show a surprisingly high sensitivity of the CD to the molecular conformation. On the other hand, the relation between CD and thermally averaged structural parameters is much less complex. While the helicity rule does not seem to hold for individual conformers, it is confirmed by the calculations for seven out of eight systems studied if thermally averaged CD spectra and structures are considered. Since thermal effects on CD can be larger than typical inherent inaccuracies of TDDFT, our results emphasize the need for a systematic treatment of conformational dynamics in CD calculations even for moderately flexible systems. Temperature-dependent CD measurements are very useful for this purpose. Our results also suggest that CD spectroscopy may be used as a sensitive probe of conformational dynamics if combined with electronic structure calculations.

Structure–chiroptical properties relationship in clavams: An experimental and theoretical study

“…Very recently, such a combined treatment of the ECD spectroscopy and the time-dependent density functional theory was used to investigate the structure-chiroptical properties relationship of carba-and oxacephams. 12 The obtained results pointed to a surprisingly high sensitivity of the CD to the molecular conformation. Nevertheless, the helicity rule may provide a good first guess of the absolute configuration of cepham analogues.…”

Two-dimensional electronic correlation spectroscopy of the nπ∗ and ππ∗ protein backbone transitions: A simulation study

“…This was done in Ref. [30] for a small system, but is not computationally feasible for large polypeptides. We thus added Gaussian random fluctuations to the site energies.…”

“…Gaussian broadening is then added to all optical transitions. Recently, by combining time-dependent density-functional theory (TDDFT) and molecular dynamics (MD), Frelek et al [30] have simulated the CD spectra of b-lactam averaging over conformational fluctuations of molecular geometries.…”

Assignment of the absolute configuration of zwitterionic and neutral macropodumines by means of TDDFT CD calculations

“…In this latter case, the input structures were generated through an MM-based conformational search sampling followed by DFT geometry optimizations. [48][49][50][51][52][53][54][55][56] The solid-state method offers the advantage of reducing the uncertainty related to-and the computational effort needed for-modeling a conformer distribution in solution. In fact:…”