Protein Conformational Complexity and Metalloenzyme Catalysis: A Combined Molecular Dynamics and QM/MM Study

Enzymes are biological catalysts - molecules that speed up chemical reactions but do not undergo transformation themselves. Most enzymes are proteins, polymers of amino acids, that wrap into complex three-dimensional structures. The enzymes of interest here also contain transition metals, which participate in the chemical reactions. The aim of the work in the proposal is to study how changes in the conformations of the enzymes - the detailed way in which they wrap up in space - can influence their reactivity. To do this, we need to combine theoretical methods that are suited to explore the conformational changes - molecular dynamics and related techniques - and those well suited to describing chemical reactions of transition metal species - combinations of quantum mechanical and molecular mechanical techniques known as QM/MM methods. We will further also analyze the molecular dynamics simulations to recognize conformational change using statistical models called Markov Models. The target enzymes are mostly cytochrome P450 enzymes, with the prospect of understanding how these enzymes are regulated.