Resolving protein conformational kinetics from single-molecule fast flicker data

Cell Reports Physical Science(2024)

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Abstract
Single-molecule experiments have demonstrated the stochastic nature of protein dynamics, spanning a broad range of space and time. However, faster conformational transitions relative to measuring rates are recorded as unresolved flicker signals, and conventional time-domain methods are intractable for analysis. Here, we establish an analytical method for extracting rate constants of proteins’ conformational changes from flicker data. An amplitude histogram compiled from flicker data retains kinetic information in its histogram shape, which is fitted with a beta distribution for deducing rate constants. Simulation studies reveal a robust capability of the method for estimating fast flicker rates overwhelming the recording frequency. We examine the single-channel current of the KcsA potassium channel undergoing flicker blocking by a quaternary ammonium and obtain the blocking rate constants. The results indicate that our analytical method is generally useful for single-molecule data and substantially extends the temporal resolution of single-molecule analyses.
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Key words
single-molecule experiments,single-channel current recordings,flicker signal,digital filter,beta distribution,rate constants,amplitude histograms,channel blocking,KcsA channel,tetrapropylammonium
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