Biological
macromolecules often exhibit correlations in fluctuations
involving distinct domains. This study decodes their functional implications
in RNA–protein recognition and target-specific binding. The
target search of a peptide along RNA in a viral TAR–Tat complex
is closely monitored using atomistic simulations, steered molecular
dynamics simulations, free energy calculations, and a machine-learning-based
clustering technique. An anticorrelated domain fluctuation is identified
between the tetraloop and the bulge region in the apo form of TAR
RNA that sets a hierarchy in the domain-specific fluctuations at each
binding event and that directs the succeeding binding footsteps. Thus,
at each binding footstep, the dynamic partner selects an RNA location
for binding where it senses a higher fluctuation, which is conventionally
reduced upon binding. This event stimulates an alternate domain fluctuation,
which then dictates sequential binding footstep/s and thus the search
progresses. Our cross-correlation maps show that the fluctuations
relay from one domain to another specific domain until the anticorrelation
between those interdomain fluctuations sustains. Artificial attenuation
of that hierarchical domain fluctuation inhibits specific RNA binding.
The binding is completed with the arrival of a few long-lived water
molecules that mediate slightly distant RNA–protein sites and
finally stabilize the overall complex. The study underscores the functional
importance of naturally designed fluctuating RNA motifs (bulge, tetraloop)
and their interplay in dictating the directionality of the search
in a highly dynamic environment.
Biological macromolecules often exhibit correlation in fluctuations involving distinct domains. This study decodes their functional implications in RNA-protein recognition and target-specific binding. The target search of a peptide along RNA in viral TAR-Tat complex is closely monitored using atomistic simulations, steered molecular dynamics simulations, free energy calculations, and a machine-learning-based clustering technique. An anti-correlated domain fluctuation is identified between the tetraloop and the bulge region in the apo form of TAR RNA that sets a hierarchy in the domain-specific fluctuations at each binding event and that directs succeeding binding footsteps. Thus, at each binding footstep, the dynamic partner selects an RNA location for binding where it senses higher fluctuation, which is conventionally reduced upon binding. This event stimulates an alternate domain- fluctuation which then dictates sequential binding footstep/s and thus, the search progresses. Our cross-correlation maps show that the fluctuations relay from one domain to another specific domain till the anti-correlation between that inter-domain fluctuations sustains. Artificial attenuation of that hierarchical domain fluctuation inhibits specific RNA binding. The binding is completed with the arrival of a few long-lived water molecules that mediate slightly distant RNA-protein sites and finally stabilizes the overall complex. The study underscores the functional importance of naturally designed fluctuating RNA motifs (bulge, tetraloop) and their interplay in dictating the directionality of the search in a highly dynamic environment.
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