NERSC Initiative for Scientific Exploration (NISE) 2011 Awards

Proton-coupled electron transfer in photocatalysis and protein translocation in biosynthesis: Bridging lengthscales and timescales in molecular simulation

Thomas Miller, California Institute of Technology

Associated NERSC Project: Sampling diffusive dynamics on long timescales, and simulating the coupled dynamics of electrons and nuclei (m822)

We aim to develop and employ novel simulation techniques to advance the understanding of photosynthetic water splitting and protein targeting in cells. Key applications of this research include the chemistries of energy and health.

Research Aim 1. Proton-coupled electron transfer in enzyme and biomimetic catalysis

Proton-coupled electron transfer (PCET) reactions are central to the chemistry of energy conversion, respiration, and enzyme kinetics. But key aspects of the kinetics and mechanism of PCET remain poorly understood due to the coupling of intrinsically quantum motions to the slower, classical motions of the surrounding environment. We propose to employ the large-scale NERSC computational resources to perform direct simulations of these processes to reveal the detailed mechanisms and the nature of the dynamic coupling between the environment and the transferred quantum particle(s). In particular, we propose path-integral molecular dynamics simulation studies of PCET dynamics in solvated iron bi-imidizoline complexes, which are a key prototype for bioinorganic catalysis and an important model system for understanding solar photocatalytic water splitting in photosystem II.

The Miller group has recently extended the ring polymer molecular dynamics (RPMD) method to directly simulate the coupled dynamics of electrons and nuclei in complex systems. The RPMD method uses the Feynman path integral formulation of statistical mechanics to map quantum mechanical particles onto an isomorphic classical mechanical system. We have demonstrated the model provides an accurate description of excess electron diffusion in liquids, the dynamics of electron localization and trapping following high-energy injection, the dynamics and kinetics of electron transfer between explicitly solvated metal ions, and the dynamics of hydride-transfer in the dihydrofolate reductase enzyme with over 14,000 atoms. By combining RPMD with conventional classical molecular dynamics technology, including rare-event sampling methods such as transition path sampling and transition interface sampling, we have demonstrated that massively parallel computational resources can be efficiently utilized to extract the mechanism and kinetics of reactions involving coupled electronic and nuclear degrees of freedom. The proposed RPMD studies of iron bi-imidizoline complexes will yield breakthroughs in our understanding of the PCET mechanism by providing the first direct simulations of PCET in a molecular system.

Research Aim 2. Sec-facilitated protein translocation and membrane integration

The Sec translocon is the central molecular component in protein targeting pathways that encompass all kingdoms of life. It is a hetero-trimeric complex of membrane-bound proteins that forms a passive channel for post-translational and co-translational protein translocation, as well as the co-translational integration of proteins into the phospholipid bilayer. The translocon operates in collaboration with molecular motors that provide the driving force for insertion of peptides into the channel. In the co-translational pathway, the peptide substrate is driven into the translocon by the bound ribosome, and in the post-translational pathway for bacteria, this role is performed by the SecA motor. Structural, biochemical, genetic, and computational studies indicate that the translocon undergoes large-scale conformational changes during both peptide secretion and membrane integration, and growing evidence suggests that SecA similarly undergoes major conformational changes to couple the hydrolysis of ATP to the peptide insertion driving force. However, basic mechanistic features of these most fundamental cellular processes remain poorly understood. The mechanism and regulation of the translocon is governed by protein-protein interactions and slow conformational changes. Critical aspects of the translocon regulation mechanism are not possible to address without simulations that span the slowest relaxation timescales for the channel/motor/substrate complex. We propose the use of large-scale NERSC simulations to address two such aspects. First, we have developed a new coarse-grained simulation approach that enables us to span the timescales for direct simulation of protein translocation and membrane integration via the Sec translocon; we propose to use this coarse-grained approach to discover the molecular origin for the dependence of translocon regulation on substrate sequence and charge distribution. Secondly, we propose atomistic simulations using enhanced sampling techniques to accurately characterize the free energy landscape for the translocon and to predict translocon and substrate mutations that will inhibit and re-direct the cellular pathways for protein secretion and membrane integration.

With adequate computational resources, such as those available on the NERSC systems, we are ready to begin the critical applications described above. The NERSC Initiative for Scientific Exploration award will be instrumental in our efforts to elucidate biological and synthetic pathways for transport and catalysis.