Progress and challenges in simulating and understanding electron transfer in proteins

This Review presents an overview of the most common numerical simulation approaches for the investigation of electron transfer (ET) in proteins. We try to highlight the merits of the different approaches but also the current limitations and challenges. The article is organized into three sections. Section 2 deals with direct simulation algorithms of charge migration in proteins. Section 3 summarizes the methods for testing the applicability of the Marcus theory for ET in proteins and for evaluating key thermodynamic quantities entering the reaction rates (reorganization energies and driving force). Recent studies interrogating the validity of the theory due to the presence of non-ergodic effects or of non-linear responses are also described. Section 4 focuses on the tunneling aspects of electron transfer. How can the electronic coupling between charge transfer states be evaluated by quantum chemistry approaches and rationalized? What interesting physics regarding the impact of protein dynamics on tunneling can be addressed? We will illustrate the different sections with examples taken from the literature to show what types of system are currently manageable with current methodologies. We also take care to recall what has been learned on the biophysics of ET within proteins thanks to the advent of atomistic simulations.