Accurate free energy calculations for biomolecular catalysis of electron transfer

Long- and short-range electron transfer (ET) between proteins is vital for all living systems, and plays an essential role in photosynthesis and bio-assimilation. ET is a central process for the transfer and storage of solar energy in advanced materials as well. Our understanding of the corresponding biological electron transport can inspire new approaches for developing and advancing energy efficient technologies. However, robust, accurate, and predictive underlying theoretical and computational models are still needed to determine structure, energetics and kinetics of ET processes in materials and biological systems.

We introduced a new analysis method, DHAM, which can be used to calculate rates and free energies from biased or unbiased simulation trajectories (Rosta and Hummer, JCTC 2015). The DHAM method is a generalisation of the current state-of-the-art weighted histogram analysis method (WHAM), which is widely used to obtain accurate free energies from biased molecular simulations. We showed that WHAM-computed free energies can exhibit significant errors, e.g. when analysing simulations under weak bias - a problem overcome by using DHAM. Our method is designed to determine a global Markov chain based on a maximum likelihood approach to analyse multiple simulation trajectories. We construct the Markov transition matrix along a discretized reaction coordinate, and obtain the corresponding stationary distribution to determine the free energy profile. Importantly, our formalism provides kinetic information of biased simulations. By building on this approach, my main aim is to develop a new method to study electron transfer.

As a first application, we will study the catalytic reaction of FNR, a central enzyme in the final step of the photosynthetic electron transfer processes using the energy of light to store high-energy electrons in the form of chemical bonds in NADPH. Our novel computational methods will provide accurate free energies as well as kinetic information about the dynamics of the photosynthetic systems. Importantly, it will allow us to understand the underlying mechanism, including the elusive coupled proton transfer steps that occur together with the electron transfer reactions in FNR.

Academia
Our results are shared via workshops, tutorials, conferences and seminars. Computational groups will be able to download our newly developed programs from my research group website (www.rostaresearch.com), or from CCPBioSim workshop/tutorial webpages. Our experimental collaborators will benefit from the more accurate and efficient algorithms that we can subsequently apply to design novel materials and test experimental hypothesis. We will work closely with Prof. Milagros Medina's group, who is an internationally known expert in FNR molecular studies. On longer term, we will apply our developed methods on additional systems, including uric acid oxidase in collaboration with Dr. Roberto Steiner (KCL). Furthermore, I have on-going collaborations with Profs. Oren Scherman and Jeremy Baumberg (Cambridge) with three papers submitted to date. Our newly developed methods will be useful in the design of novel nanomaterials in currently on-going collaborative projects.

Public Sector, Business, Industry
On long term, health-related public sectors will benefit from basic research on structure and function of FNR, or other e.g., phosphate processing enzymes. Our methods can be used and may be inspirational to a large number of projects studying the dynamics of phosphate-processing enzymes that are relevant to many diseases. Phosphate processing enzymes are validated targets of a large number of drugs used in current clinical practices treating a wide range of diseases. These include reverse transcriptase and integrase inhibitors used against HIV and hepatitis B, proton pump inhibitors used in gastric diseases, kinase and topoisomerase inhibitors used in chemotherapy to treat cancers.
In particular, BRAF inhibitor drugs are recent examples of targeted cancer therapy: (http://www.cancer.gov/cancertopics/treatment/types/targeted-therapies/targeted-therapies-fact-sheet). In our on-going projects on BRAF dynamics studies together with Prof. Walter Kolch-s (Director, Systems Biology Ireland and Conway Institute) group, we are already using the DHAM method, and our future algorithms will be highly beneficial as well. This project is carried out also in collaboration with researchers from Genentech, who kindly provided drug molecules for experimental validations of our computational results.
Our basic research results are also relevant to UK charities such as Cancer Research UK. In addition to drug design, insights related to controlling enzyme activity is also relevant for biotechnology industries, e.g., businesses developing industrial enzymes such as Novozymes.

General Public, Education
The general public, high school and university students will benefit from new basic research developments in general, by public lectures in the UK and world-wide (e.g., via the Alchemy Today seminar series of the Eotvos University, where I've been invited as a speaker), or by the Open Days at King's. My lab also hosted 9 high school students to date in the past three years, who were introduced to on-going research in my lab via the In2Science and Nuffield Research Placement programs.