Structural Chemistry

Proteins containing tetrapyrroles are one of the most common enzyme motifs found in nature. The involvement of the same porphyrin cofactor in quite distinct chemical reactions, biological functions or medical processes indicates the importance of conformational changes in the porphyrin macrocycle to the function of the enzyme.

One of our ongoing aims is to understand the structural and conformational parameters of porphyrins in order to elucidate the relationship between macrocycle conformation, physicochemical properties and biological function.

Previous work on analysis of various porphyrin-protein structures has revealed that the chlorophylls in the photosynthetic antenna and reaction center complexes possess distinct tetrapyrrole conformations. The macrocycles found in the heme proteins of respiration show considerable range of motion and flexibility, depending on environment, spin state, and axial ligands and domed, planar or ruffled porphyrins have been identified in vivo. Similar results were found for cytochromes involved in electron transfer reactions. Evidence for a high degree of conformational flexibility in vitamin B12 derivatives and other corrins was also found and very specific conformational changes have been identified for the sirohemes present in nitrite and sulfite reductase.

Our research focus is the synthesis of novel, conformationally designed porphyrins for studying the interplay between macrocycle conformation and physicochemical properties. Most of the past biomimetic studies were performed with easily accessible symmetric porphyrins, where one type of distortion mode determines the overall conformation. While these systems have provided a wealth of information they are far removed from the natural situation. Natural systems tend to have an unsymmetric substituent pattern and an asymmetric protein environment and so show a mixing of different distortion modes. We are constantly designing porphyrins in such a way that the steric and electronic effects of proteins are mimicked by peripheral substituents attached to the porphyrin. Porphyrins with different types, number, and regiochemical arrangement of substituents have, and will continue to be, synthesized by us. To identify the conformational effects of individual substituents we analyze the Ax-porphyrin series where the residues are alkyl and aryl residues of different steric demand (e.g., the n-, sec-, iso-, and tert-butyl series).

The conformation of these porphyrins in the solid state is primarily investigated by X-ray crystallography and vibrational spectroscopy. Analysis focuses on the identification of core structural and conformational parameters such as core size, out-of-plane distortions, core elongation, twist angles, etc. Special attention is given to delineate the electronic effects of the substituents from their steric effects.

There are several approaches to preparing nonplanar porphyrins that mimic the situation in nature. These include sterically overloading the periphery of porphyrin, metal and axial ligand effects, manipulation of the core and strapping. The Senge group has significantly contributed to this area of research. Porphyrins with two or more different meso-substituents can be used to elucidate the influence of individual substituent types on the mixing of various distortion modes. Further modulation of the steric (meso-R = Ar, alkyl, F, Cl) or electronic effects (CN, NO2) is possible. Synthetically these porphyrins are accessible via direct substitution reactions (developed by the host laboratory), Pd catalyzed coupling reactions of bromo-porphyrins and electrophilic halogenation reactions starting from either beta- or meso-substituted porphyrins.

The proposed analysis of the interrelationship between conformation and function has implications for a wide range of different biological processes, pathological processes, clinical applications and for the efforts now devoted to biomimetic solar energy conversion, catalysis, cancer therapy, as well as basic mechanisms of electron transfer. Efforts to prepare asymmetric nonplanar porphyrins or systems more akin to the situation in vivo have only recently begun and in the field of photosynthesis, efficient mimics are still lacking.