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Multiscale Modeling of Metalloenzymes: Design and Evolution

  • Author(s): Nechay, Michael
  • Advisor(s): Alexandrova, Anastassia A
  • et al.
Abstract

With just a simple alphabet of natural amino acids and common metals, enzymes perform a spectacular number of reactions necessary for life on earth with enviable ease – with neither the extreme conditions nor chemical waste seen from many industrial reactors in human-developed catalysis. Principally, protein structure and related function is not well understood beyond being decisive for its unique selectivity and efficiency. A reliable treatment of larger protein movements/sampling coupled with precise quantum mechanical treatment of metals and bonds breaking/forming (multiscale) is still an open problem in Computational Chemistry. Metalloenzymes can be particularly challenging to model so we present some of the latest in multiscale modeling techniques. We have developed methods sensitive enough to study “selection” of similar metals in enzymes such as HDAC8, where previous literature failed to conclude which metal is active during in vivo catalysis, while fast enough to study larger protein movements including fold stability.

Eminently, multiscale modeling opens the discussion of engineering enzymes to cater to modern day needs in catalysis. Society has not only developed needs in catalysis outside the scope of natural evolution (e.g., drug synthesis, energy conversion) but also has access to more of the periodic table than nature has had a chance to explore. Thus, combining the efficacy of natural enzymes with modern catalytic processes has enormous potential. We have studied iridium, a rare metal with thermodynamic advantages over other metals in promoting catalysis of hydroamination and transfer hydrogenation. In the context of an enzyme we predict catalytic rates near and even exceeding existing organometallic catalysts with further design for specificity available. We are in collaboration with an experimental group in designing a protein fold which both directly accommodates and uses iridium in catalysis. We hope these foundations will support metalloenzyme design efforts towards novel chemical transformations performed as efficiently and environmentally soundly as nature has shown us is possible.

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