Accurate free energy calculations for biomolecular catalysis of electron transfer

Lead Research Organisation: King's College London
Department Name: Chemistry

Abstract

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.

Planned Impact

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.

Publications

10 25 50
publication icon
Badaoui M (2018) Calculating Kinetic Rates and Membrane Permeability from Biased Simulations. in The journal of physical chemistry. B

publication icon
Carnegie C (2018) Room-Temperature Optical Picocavities below 1 nm Accessing Single-Atom Geometries. in The journal of physical chemistry letters

publication icon
Del Barrio J (2016) Light-Regulated Molecular Trafficking in a Synthetic Water-Soluble Host. in Journal of the American Chemical Society

publication icon
Kells A (2018) Limiting relaxation times from Markov state models. in The Journal of chemical physics

publication icon
Leahy CT (2016) Coarse Master Equations for Binding Kinetics of Amyloid Peptide Dimers. in The journal of physical chemistry letters

publication icon
Martini L (2017) Variational Identification of Markovian Transition States in Physical Review X

 
Description Modern computers are powerful tools to model biomolecular processes. However, the timescales required to reach to observe key events are still too long to reach even using high performance computing clusters. We developed new tools to use enhanced sampling simulation protocols and obtain key timescales from these biased simulations, as well as to analyse simulation trajectories based on dynamic properties and identify rate determining transition states. We applied these novel methods on a number of biomedically important systems, such as in cytochrome c oxidase, lipoxygenases, amyloid peptides, etc to determine kinetic and energetic properties. We also applied our computational tools to help design novel host-guest systems and nanoscale functional materials.
Exploitation Route Our algortihms may be used in rational design of drugs based on molecular kinetics. Novel nanoscale synthetic systems could be used creatively in various applications that are based on catalysis, photochemistry, etc.
Sectors Energy,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description Calculation of kinetic rates directly from atomistic molecular simulations
Amount £20,000 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 07/2016 
End 03/2017
 
Description Novel Enhanced Sampling Methods in Multiscale Modeling
Amount £819,960 (GBP)
Funding ID EP/R013012/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 09/2018 
End 09/2023
 
Description Programme Grant
Amount £8,649,438 (GBP)
Funding ID EP/L027151/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 10/2017 
End 10/2018
 
Description Collaboration with Prof. Jose Maria Lluch's group 
Organisation Autonomous University of Barcelona (UAB)
Country Spain 
Sector Academic/University 
PI Contribution We helped to carry out and analyse QM/MM MD simulations using umbrella sampling bias, and calculated the kinetics as well as the free energies of the catalytic reaction to obtain the Arrhenius prefactor.
Collaborator Contribution Patricia Laura, a PhD student was awarded funding to visit my group and work in my lab.
Impact Joint publication by Suardiaz et al, J. Chem. Theor. Comput. 2016, DOI: 10.1021/acs.jctc.5b01236.
Start Year 2015
 
Description Collaboration with the Nano-Optics to controlled Nano-Chemistry programme 
Organisation University of Cambridge
Department Cavendish Laboratory
Country United Kingdom 
Sector Academic/University 
PI Contribution Our team performs electronic structure calculations to validate and design experiments in our collaborator groups led by Profs. Oren Scherman and Jeremy Baumberg in Cambridge.
Collaborator Contribution We have several joint publications already.
Impact Chikkarady et al, Nature, 2016, DOI: 10.1038/nature17974 In collaboration with the nano-optics lab - led by Prof. Jeremy Baumberg. Del Barrio et al, J. Am. Chem. Soc., 2016, DOI: 10.1021/jacs.5b11642 Ryan et al, Angewandte, 2016, DOI: 10.1002/anie.201607693 McCune et al, Org. Biomol. Chem., 2017, DOI: 10.1039/c6ob02594c Synthetic chemistry and materials reseach on host-guest supramolecular chemistry - led by Prof. Oren Scherman.
Start Year 2015
 
Description Collaboration with the Nano-Optics to controlled Nano-Chemistry programme 
Organisation University of Cambridge
Department Department of Chemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution Our team performs electronic structure calculations to validate and design experiments in our collaborator groups led by Profs. Oren Scherman and Jeremy Baumberg in Cambridge.
Collaborator Contribution We have several joint publications already.
Impact Chikkarady et al, Nature, 2016, DOI: 10.1038/nature17974 In collaboration with the nano-optics lab - led by Prof. Jeremy Baumberg. Del Barrio et al, J. Am. Chem. Soc., 2016, DOI: 10.1021/jacs.5b11642 Ryan et al, Angewandte, 2016, DOI: 10.1002/anie.201607693 McCune et al, Org. Biomol. Chem., 2017, DOI: 10.1039/c6ob02594c Synthetic chemistry and materials reseach on host-guest supramolecular chemistry - led by Prof. Oren Scherman.
Start Year 2015
 
Description Markov modelling and free energy calculation workshop 2016 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact About 50 participants attended the Markov modelling workshop we organised at King's College London, some of which were international scientists from India, Europe or the US. Several participants were from pharmaceutical companies, such as Novartis, GSK, and UCB Pharma. The workshop initiated further collaborations and research visits with both academic groups and pharma companies.
Year(s) Of Engagement Activity 2016