Modeling Fluorescence Observables, Particularly for FRET Experiments, using Markov Chain Analysis of Molecular Dynamics and Quantum Mechanics Simulations

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We present a new method for simulating fluorescence observables, particularly those related to bulk and single-molecule fluorescence-detected resonance energy transfer (FRET) experiments. In this method, a molecular dynamics (MD) simulation is used to sample configuration space and quantum mechanics (QM) calculations are used to estimate the electronic coupling between the donor and acceptor probes for snapshots along the MD trajectory. A Markov chain method is used to sample the resulting electronic coupling trajectory allowing accurate simulation of any desired fluorescence observables, such as FRET efficiency histograms or time-resolved donor fluorescence decays. The Markov chain results will be compared with the results of simple histogram and averaging schemes showing that the Markov chain is the only one that yields realistic results in well known examples such as the rapid diffusion limit. This combination of computational methods also avoids some pitfalls of traditional FRET analysis such as the kappa-squared and the ideal dipole approximations. Because the simulation results can be compared directly with experimental observables, this method may allow more detail to be derived from experiment than is traditionally possible.