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Can escape times reveal hidden steps in an energy landscape?

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How quickly the fastest particles or molecules finish a journey reveals how many intermediate resting states they must pass through, and roughly how deep those states are.

Source

Direct detection of molecular intermediates from first-passage times

Thorneywork AL, Gladrow J, Qing Y, et al. · Science advances · 2020

doi.org/10.1126/sciadv.aaz4642Read the full paper ↗33 citationscc by

Study at a glance

Design
Other — Colloidal particles diffusing in microchannels with optical-trap potential minima; first-passage time distributions compared with a network-theory prediction, then applied to two molecular datasets
N
Colloid datasets of 500 to 4000 trajectories each; nanopore hopper gave 161 two-hop and 87 three-hop events
Population
Polystyrene colloids in microfluidic channels; a DNA-cargo nanopore hopper; DNA hairpins in optical tweezers
Outcome
Short-time slope of the log-log first-passage time distribution and length of the power-law regime

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What they did

The authors trapped colloidal particles in narrow microfluidic channels and used holographic optical tweezers to place weak traps along them, creating known energy landscapes with one, two or three minima to cross. They measured how long particles took to exit (first-passage times) and plotted the distributions on log-log axes. They then applied the same analysis to existing data on a molecular hopper ratcheting DNA through a nanopore and on DNA hairpins folding and unfolding.

What they found

At short times each distribution followed a power law whose integer slope equalled the number of intermediate minima crossed, as predicted by theory for networks of states. The duration of this power-law regime grew exponentially with trap depth, so it also encodes how deep the minima are. The nanopore hopper and the two DNA hairpins showed slopes of about 1 and 2, matching their known numbers of intermediate states, and the hopper data implied a well depth of about 17 kT.

The limits

What it doesn't show

The method recovers only the number and depth of minima along the shortest path, not the full shape of the landscape. It needs minima clearly deeper than thermal energy and good time resolution; shallow traps blurred the power law, and a slope counts only the minimum number of states, so shallower extra minima could be hidden. The m = 3 case for the nanopore had too few events to resolve, and the absence of a power law is hard to interpret.

Key terms

First-passage time
The time a randomly moving system takes to reach a chosen target state or boundary for the first time.
Energy landscape
A map of potential energy against position or configuration whose valleys are stable or intermediate states.
Optical tweezers
Focused laser beams that trap and move small particles using light forces.
Power law
A relationship y proportional to x raised to a power, which appears as a straight line on log-log axes.
Markov jump model
A description where a system hops between discrete states with no memory of its past, valid when it spends much longer in states than moving between them.

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Quiz yourself

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On a log-log plot, what reveals the number of intermediate minima?

Common questions

Why use colloids instead of molecules to test the idea?

With colloids and optical traps the energy landscape is known and controlled and every position is tracked, so theory can be checked directly before applying it to molecules.

Why do only short times matter for counting states?

The shortest escapes are those that go straight through without lingering or back-tracking, and their probability scales with a power set by the number of states crossed.

Can the method reconstruct the whole landscape?

No. It gives the number of intermediate minima and an estimate of their depth, which the authors argue are the most important features for dynamics.

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