What is it about?

THE THERMODYNAMIC SINGLE-MOLECULE DEMON (Maxwell's Demon) IS IN YOUR SINGLE-MOLECULE EXPERIMENTS IN DILUTE LIQUDS AND LIVE CELLS WITHOUT IMMOBILIZATION OR HYDRODYNAMIC FLOW: How far apart do two molecules / two particles have to be in the time domain so that the required degree of separation between the two individual molecules / the two individual particles can be quantified at the molecular scale in order to distinguish them as separate entities without immobilization or hydrodynamic flow? Enjoy the real world of physics! Since mathematics provides a way to answer questions about the thermodynamic jitter in a clear, rational manner, with evidence to support it, mathematics is the reliable method necessary to get the best information on the movement of a single molecule / a single particle at the molecular scale in dilute liquids and live cells without immobilization or hydrodynamic flow.

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Why is it important?

It is the Theory of Single-Molecule Biophysics & Biochemistry Based On the Stochastic Nature of Diffusion. A theory has only the alternative of being right or wrong (Manfred Eigen, Nobel Prize winner). Földes-Papp's thermodynamically temporal single-molecule limits, or Földes-Papp's temporal resolution in diffraction limited and unlimited optical systems for dilute liquids or live cells without immobilization on a solid phase or membrane as well as without significant hydrodynamic flow,or even shorter, Földes-Papp's limits are the reference measures (so called 'golden standard') for any temporal resolution calculations/algorithms based upon parameter sets of (specific) measurement techniques, for example, photon counting statistics, Nyquist limit, FRET, etc., in order to ultimately justify whether or not a single molecule/particle (individual molecule/particle, selfsame molecule/particle) was measured during the observation/detection time in dilute liquids or live cells without immobilization on a solid phase or membrane as well as without significant hydrodynamic flow. Földes-Papp's limits are limits in measurement times that should not be exceeded when one wants to follow the selfsame molecule with high probability. Richard Levenson, Professor and Vice Chair for Strategic Technologies, Dept. at UC Davis, Davis, California, USA, wrote to me on May 24, 2021: ‘Much easier on Pluto, I imagine. A very cold, former planet. Not too much thermodynamic jitter at -233 C.’

Perspectives

Conclusions - Perspectives and Difficulties: As a theoretical and experimental concept, the meaningful time Tm and Tm(t) are something that becomes more complicated the longer we focus on it. We deal with three types of meaningful times: i) the meaningful time as quantitative measure for the meaningful re-entries of the same single molecule/same single particle in the observation/detection volume, ii) the meaningful time as single molecule/single particle time resolution and iii) the meaningful time as limits in measurement time that should not be exceeded when one wants to follow the same single molecule / same single particle with high probability in one, two or three dimensions. The dimensions of the meaningful times are the dimensions of the diffusion times of the molecule/particle in liquids and live cells without immobilization or/and without significant hydrodynamic flow. But this also seems to be thermodynamically violated in the single molecule literature of freely diffusing molecules in liquids, live cells, biological and artificial menbranes, etc.. What do the approaches of single molecule localization microscopy/nanoscopy (super-resolution microscopy/spectroscopy), single molecule laser scanning microscopy, single molecule image analysis, single molecule FRET (fluorescence resonance energy transfer), fluorescence correlation spectroscopy at the single molecule level or dual-color fluorescence cross-correlation spectroscopy at the single molecule level, and so on in liquids or live cells without immobilization on artifcial or biological surfaces or without significant hydrodynamic flow tell us about a single molecule or a single particle [8, and, for example, references given therein]? The sober and honest answer is: NOTHING after so many years of unsuccessful attempts [8]. At best, these are misleading and naive phrases in order to be able to sell and promote trendy and mediocre research results in reputable journals. By means of the equation (16) in ref. [11], the number of molecules / particles over which was averaged can be calculated. Basically, the single molecule time-resolution is the counterpart of the space-resolution in optical diffraction-limited microscopy imposed by the Wave Nature of Light and first established by Ernst Abbe's wellknown formula in 1873 and later refined by Lord Rayleigh in 1896 to quantitate the measure of separation necessary between two Airy patterns in order to distinguish them as separate entities. We should enjoy the real world of physics, which is complicated and NOT MINIMALIST. A minimalist model has a third possibility, it may be right but irrelevant. This is especially valid for real diffusive processes in live cells as shown in the section ANOMALOUS DIFFUSION BASED ON CTRW IN CROWDED ENVIORNMENTS of this original article.

Professor Zeno Földes-Papp [Biochemist, Gerontologist (Biochemiker, Geriater)]: Single-Molecule Biophysics & Biochemistry Based On the Stochastic Nature of Diffusion
Head of Geriatric Medicine (Medical Director of the Geriatric Service: Sektionsleitung Geriatrie) at Asklepios Klinikum Lindau (Bodensee), Bavaria, Germany

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This page is a summary of: Getting high on single-molecule biophysics and biochemistry in dilute liquids and live cells without immobilization or significant hydrodynamic flow: the thermodynamic single-molecule demon, Current Pharmaceutical Biotechnology, June 2022, Bentham Science Publishers, DOI: 10.2174/1389201023666220616123928.
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