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Open review of biodynamic neutron scattering publications

by Wolfgang Doster
a unique Website devoted to graduate students, postdocs and all enthusiasts of Neutron Spectroscopy.
The post-Sankt Petersburg ECNS 2019 edition

Scope:
The peer-review of a scientific manuscript is not open. It occurs behind closed doors. The referees and Editors of scientific journals thus decide in a highly intransparent procedure, whether a manuscript is interesting enough and suitable for publication or not. The arguments remain secret. Their judgement is often biased by special interests, in particular off-main stream papers tend to be suppressed. The referee system is easily corrupted to reduce critical discussions and to exclude competitors. A recent submission to JCP was rejected, because we did not remove a critical discussion of related literature as requested. Once a paper has been published, even if it is obviously wrong, it is considered as established truth, writing critical comments is tedious and time consuming. One of my comments, concerning a basic mathematical error, was processed three times against the vote of the authors by JCP, before it was published. The alternative would be a system of open reviews, practiced partially by PNAS, making it easier to get published, but at the same time, Comments would be facilitated to initiate a scientific discussion.

The motivation of this Website is to document the unusually large number of scientifically questionable papers in bio-neutron scattering, published in high ranking journals like PNAS, PRL, BJ. Here I illustrate the idea of open critical reviews with published papers, where the referee system has obviouly failed. As the victim of a citation blockade, I found it increasingly difficult, to publish alternative and critical views in main stream journals.
Neutron scattering is an open access technique, which is provided by large scale facilities such as the FRM 2 in Garching
FRM2. Biological inelastic neutron scattering can yield information on hydrogen based protein structural fluctuations and hydration water on a pico to nano-second time scale, comparable to the range covered by MD simulations.
Open access means that people with interesting ideas can get beam time, without demonstrating, that their knowledge of the technique is sufficient to perform such experiments. This aspect may account in part for the above mentioned deficiencies.

Background:

The field was initiated in 1989 by the "Nature Milestone" paper of Doster et al., "Dynamical transition of myoglobin revealed by inelastic neutron scattering". It was my second NS paper out of 30, the first one was with Martin Karplus. It showed for the first time wide temperature and frequency range spectra of a hydrated protein, combining data derived with two spectrometers IN6 and IN13 at the ILL in Grenoble. A small fraction of this paper was devoted to the Q and temperature dependence of elastic scattering, displaying two "dynamical transitions" near 160 and 240 K. At the transition temperature the relaxation times of protein motions overlap with the respective instrumental observation time.
During the next 30 years only the elastic section was picked up in 90 % of the citations, the equally important inelastic component was largely ignored:
G. Zaccai had the "ingenious" idea to reduce biodynamic neutron scattering to elastic scans. This approach can be justified for particular applications, specially if the biological material is available only in minor quantities ERS2003. From elastic scans a very useful molecular quantity, the "mean square displacement" can be deduced by fitting the data at low Q to straight lines.
This simple method convinced many biologists, experienced in static low angle scattering, to consider dynamic aspects. The possibility to deduce "biological dynamics" from elastic scattering experiments, boosted the field with a flood of publications. Not all of them were of high quality.
To cite a paper without reading it completely can be dangerous. For the "dynamical transition" the spectral analysis demonstrated that the nonlinear onset in the displacements at 240 K was resolution controlled. Thus with their "elastic only analysis", a wide range of questionable interpretations was possible..

Ignored problems:

(1) Most important, the elastic scans had to cover a wide temperature range, far below room temperature to spot the "dynamical transitions". To avoid ice formation, this required "hydrated" instead of solvated samples. The properties of solvents at low temperatures can lead to strange effects of demixing, ice formation and glass transitions, explaining some questionable interpretations. It was shown, that the "dynamical transition" can be recorded at room temperature by the new technique of "elastic resolution spectroscopy" with IN5 data, Doster et al. 2001. Thus also the low temperature transition at 160 K is resolution controlled and was assigned for the first time to methyl rotation.
(2) The restriction to the tiny elastic part of the spectrum near zero frequency, ignoring the rest of the energy window, reflects essentially the immobile, structurally static property of the biomolecule. Dynamics enters only via a diminishing elastic intensity with increasing temperature.

(3) Another problematic restriction is the focus on the narrow Q-range near zero momentum exchange, to derive mean square displacements, assuming the "Gaussian approximation".
Many workers did not fully understand the limitations of their method, its dependence on instrumental resolution and multiple scattering: The zero Q-extrapolated intensity decreases with increasing temperature. The "factor of two problem" with the Gaussian Lamb-Mössbauer factor lead to a confusion about the correct magnitude of mean square displacements Magazu et al. 2017.

The "elastic intensity" approach recieved its final approvement, when the prestigious "Walter Hälg" prize was devoted to G. Zaccai in 2013. His publications provide very instructive examples of long lasting errors and sensational results. In his Science 2000 paper he interpreted the protein dynamical transition as resilence softening of the protein force constants. 13 years later at the "Les Houches School" , he presented the identical concept, although is was disproven by us in 1989 and many times later. G. Zaccai, Les Houches 2013 . It was the main topic of the laudatio for the prize given by J. Smith. The latter has published since 1990 a huge number of MD-papers, advertising "dynamic heterogeneity", including the "dynamical transition in a dry protein" Liu et al., PRL 2017 .

Biomolecular neutron scattering recieved a serious blow, when the nuclear physicist Hans Frauenfelder took control of the field beyond 2008, resulting in a dramatic decline of scientific quality. Now, energy landscapes and motional heterogeneity became main stream to explain bioneutron scattering. The complexity of dynamics, controlled by energy landscapes, naturally required the assistance of computer simulation. Elastic neutron scattering experiments are only needed to confirm the time resolved MD simulations. In his most recent papers (PNAS 2015/ 2017, discussed below) Frauenfelder suggests a complete re-interpretation of quasi-elastic neutron scattering theory in terms of inhomogeneous spectral broadening. Elastic scattering is dismissed. The hopping across an energy landscape is defined as the basic physical process in proteins. Spatial displacements, defining the Van Hove space-time correlation function, are replaced by diffusion in energy space. Frauenfelder, PNAS 2014.


The molecular view:

Our approach of discussing protein motions in terms of few well defined molecular components, standard in other fields (NMR), was misquoted by the heterogeneity group as a two-state model. Already in 1989 we started with two dynamic components, rotational transitions and water-coupled translational motions. Our new RT model describes wide range data successfully in the time domain without the need of low temperatures. The "protein dynamical transition" is no longer present in this model, since the data were corrected for the instrumental resolution.
It is revealing, that the respective manuscript, submitted to J. Chem. Phys. in 2018, with the provocative title, "Protein dynamics without energy landscape" was rejected, although the referees could not justify their verdict with decent scientific arguments. One referee, who sounded a lot like Hans Frauenfelder, was completely opposed to the landscape-free model: "not new", "self-citations". The second referee with MD background supported the publication, but requested to remove all critical comments to related work. This was rejected by us, since the purpose of this manuscript was to present an alternative view to dynamic heterogeneity. The Editors refused to involve a third referee, familiar with experimental neutron scattering. At the ECNS 2019 in St. Petersburg, our submitted oral contribution, a compact version of the JCP manuscript, was downgraded to the level of a Poster. By contrast, the "elastic only scattering group" recieved several invited talks from the organizers. One negative highlight was the dubious "water-protein decoupling" hypothesis of A. Benedetto, based on Q-averaged elastic scattering data (Phys. Chem. Lett. 2017). But the most scandalous talk was presented by Kearley and Benedetto on "Elastic Scattering Spectroscopy", which is a downgraded copy of what we had initially published in 2001 under the close, more appropriate name "Elastic Resolution Spectroscopy" (Doster et al. Physica B, 2001). According to their paper, elastic scattering experiments at different resolution are sufficient, after some numerical treatment, to determine the exact intermediate scattering function. This was shown to be incorrect (Doster et al. JCP, 2013). The citation blockade thus still exists, illustrating, why this Web Site is necessary.
Our new pedagogical version of how elastic and inelastic scattering with proteins can be combined, including a discussion of protein function, was published in Doster, 2018. "Are proteins dynamically heterogeneous?".


The role of errors and critical Comments to selected literature:

Said a big shot in this field to a young professor, the names are known,"in your last paper you said, I was wrong", "weren't you wrong?" "Yes, but you don't say it." This Web site is going to "say it". Hans Frauenfelder said to his postdoc: "Possibly I am wrong, but it will take them a long time to find out". Errors, according to Thomas Fermi, are quite common in Science. What matters is, how fast you find out. The philosoper Karl Popper proved, that Science proceeds essentially via disprove of errors and less by confirming results.
It is not the errors that strike me, it is their persistence and the political forces to prevent their correction.
To illustrate my point, I present below critical comments to selected publications, which contain "common" scientific errors or suggest conclusions, which are not properly justified. I emphasize, that this Web site reflects my personal view, which could be wrong, unjust or incomplete.
Of course, a lot of high quality work has been published in this field: The Berlin group around Jörg Fitter and the late Rueb Lechner combined successfully elastic and inelastic experiments to study bacteriorhodopsin, still valid today.
Another landmark paper, covering the transition from powder to solution was published by J Pérez, JM Zanotti, D Durand, Biophysical journal 77 (1), 454-469. Longeville and Stingaciu (2017) determine the role of hemoglobin diffusion inside blood cells to facilitate oxygen exchange in the lung with NSE (Sci. Rep. 7: 10448). The Munich-Jülich NSE group studies the polymer properties of partially folded proteins in the time domain, which has yielded interesting results.
Some rarely cited Doster papers: Lit.
Comments to: wdoster@bioneutron.de

2018: Protein dynamics without energy landscape: a rotation-translation model combining elastic, time domain and multiple scattering
by W. Doster and M.S. Appavou, submitted to J. Chem. Phys. in Feb. 2018
short version
rejected JCP manuscript
JCP referee comments

2018: Are proteins dynamically heterogeneous?
by W. Doster, Int. J. Mol. Theo. Phys.2(1): 1-14, 2018, open access ,
"Dynamic heterogeneity" distributions (Smith/Frauenfelder) is the alternative concept to "a discrete component" molecular view (Doster)
pdf
referee comments


2018: Franck-Condon picture of incoherent neutron scattering
by G. Kneller, PNAS 115, 94509455 (2018), attempt to justify energy landscape models of proteins with quantum theoretical arguments.
Doster, PNAS Letter Apr. 2019,
G. Keller, Response to PNAS Letter Apr. 2019,

2017: Low temperature decoupling of protein and water dynamics measured by neutron scattering
by A. Benedetto, Physical Chemistry Letters (2017)
Comment W. Doster, July 2019



2017: The role of momentum transfer during incoherent neutron scattering is explained by the energy landscape model
by H. Frauenfelder, R.D. Young, P.W. Fenimore PNAS vol 114, 5130(2017).

Doster Comment: the Frauenfelder zero Q elastic scattering effect reflects multiple scattering
and not the energy landscape

2015: Motional Displacement in Proteins, origin of wavevector-dependent values by D. Vural, L. Hong, J. Smith, H. R. Glyde, Phys.Rev. E. 91 052705(2015).
A more recent version was published by the same authors in Biophys. J. 114, 2397, 2018,
Determination of dynamical heterogeneity of proteins from dynamic neutron scattering
Comment Doster


2015: Influence of Pressure and Crowding on the Subnanosecond Dynamics of Globular Proteins, by M. Erlkamp, J. Marion, N. Martinez, C. Czeslik, J. Peters and R. Winter J. Phys. Chem B 119 4842(2015). Comment Doster


2014: Wave mechanical model of incoherent quasielastic neutron scattering in complex systems
by Hans Frauenfelder, Paul Fenimore and Robert Young, PNAS , 111, 12764 (2014).

Wuttke: No case against scattering theory, PNAS Letter
Doster Comment


2014: Does a dry protein undergo a glass transition by A. Frontzek, S. Strokov, ,J. Embs and S. Lushnikov, J. Phys. Chem B 118(11) 2791-2802(2014). Comment
(The Freeze Drying Glass Transition in Dry Proteins)

2013: Dynamics and Free Energy Landscape of Proteins, explored with the Mössbauer effect and quasi-elastic neutron scattering by Frauenfelder, Young and Fenimore, J. Phys. Chem. 117 13301 (2013)
(The Mössbauer Model of Quasi-elastic Neutron Scattering) Comment Doster



2012/2013: Change of caged dynamics of hydrated proteins by Capaccioli, Ngai, Ancherbak, Paciaroni, J. Chem.Phys. 138 (2013) 235102.
Comment Doster
Two step scenario of the protein dynamical transition
Evidence of coexistence of change of caged dynamics.. by Capaccioli, Ngai, Paciaroni, J.Phys. Chem. B 116 (2012) 1745.
submitted open Comment by W. Doster, rejected by Editor of JPCB

2011: The RENS puzzle

Elastic incoherent neutron scattering operating by varying instrumental energy resolution: Principle, simulations, and experiments of the resolution elastic neutron scattering (RENS) S. Magazu, F. Migliardo, A. Benedetto Review of Scientific Instruments 82 (10), 105115 (2011)
nearly identical: Magazu, Migliardo, Benedetto, Vertessy in Chemical Physics 424(2013)26: Protein dynamics and neutron scattering..
Comment Doster
Comment Wuttke, Rev. Sci. Instr. 2011

2011: Protein dynamical transition at 110 K, by C. Kim, M. Tate and S. Gruner PNAS 108, 20897 (2011) Comment

2011: The Frauenfelder Mössbauer effect and the PDT
Mössbauer effect in proteins, Young, Frauenfelder, Fenimore, PRL(2011)107, 158102
Comment Doster

2008: Elliptical protein phase diagrams
Pressure and temperature dependent protein stability by Widersich, Skerra, Köhler, Friedrich, PNAS 105, 575 (2008)
Comment Doster

2006: Instrumental resolution effects interpreted as a fragile-strong crossover
Observation of fragile to strong dynamic cross-over of protein hydration water by S.H. Chen, L.Liu, E. Fratini, P. Bagliaoni, A. Faraone and E. Mamontov, PNAS USA 103, 9012 (2006)
Comment Doster

2004: Frauenfelders alpha/beta relaxation
Bulk solvent and hydration shell fluctuations by Fenimore, Frauenfelder, Mc Mahon, Young PNAS USA (2004)101,14408
Comment Doster

2003: Neutron Hydrogen Displacement Distribution in Myoglobin
Hydrogen atoms in proteins, Engler, Ostermann, Nijmura, Parak, PNAS USA (2003)100,10243
Comment Doster

2002: Slaving II
Solvent fluctuations dominate protein dynamics and function
by Fenimore, Frauenfelder, Mc Mahon, Parak, PNAS USA (2002)99,16047
Comment Doster

2002: Confined water and the two simple explanation
A model for water motion in crystals of lysozyme based on an incoherent quasi-elastic neutron scattering study by C.Bon, A.J. Dianoux, M. Ferrand and M.S. Lehmann, Biophys. J. 83( 2002) 1578
Comment Doster

2002: The protein dynamical transition may have a simple explanantion
by M. R. Daniel, J. Finney and J. Smith, Faraday Discussion (2002) 122,163
Comment Doster

2000: Protein force constants from elastic displacements?
How soft is a protein? A protein dynamics force constant measured by neutron scattering by J. Zaccai, Science 288,1604( 2000)
Comment Doster

1998: Dynamic labelling of different functional parts of BR
by V. Reat, H. Patzelt, M. Ferrand, C. Pfister, D. Oesterhelt, G. Zaccai PNAS 95(1998)4970
Comment Doster

1998: Activity below the dynamic transition?
Enzyme Activity below the Protein Dynamical Transition at 220K by R. Daniel, J.Smith, M. Ferrand, S. Hery, R. Dunn, J. Finney, Biophys. J. 75 (1998) 2504
Comment Doster

1993: Melting of a frozen protein solution
Thermal motion and function of bacteriorhodopsin in purple membrane, effect of temperature and hydration observed by neutron scattering by M. Ferrand, A. Dianoux, W. Petry an G. Zaccai, PNAS 90, 9668 (1993)communicated by Hans Frauenfelder.
Comment Doster


1992: Confined water (I):
Single particle dynamics of hydration water in protein, M.C. Bellissent-Funel, J. Teixera, J.F. Bradley, S.H. Chen and L. Crespi, Physica B 181 &181, 740 (1992).
Comment

1991: Review Article on MD Simulation and Experiments
Protein Dynamics: comparison of simulations with inelastic neutron scattering experiments, by J. Smith, Quat. Rev. Biophys.24 (1991), 227
Comment Doster

1991: Frauenfelders Energy Landscapes
The energy landscapes and motions in proteins, H. Frauenfelder, S. Sligar and P. Wolynes, Science 254 (1991) 1598
Comment

1990: Vacuum simulation of a hydrated protein
Dynamics of myoglobin: comparison of simulation results with neutron scattering spectra, by J. Smith, K. Kuczera and M. Karplus, PNAS USA (1990)87, 1601.
Comment Doster

1990:The temperature dependence of dynamics of hydrated myoglobin, comparison of force field calculations with neutron scattering data by R. Loncharich and B. Brooks, J. Mol. Biol. (1990)215, 439

1989: first spectral analysis of protein dynamics:
Dynamical transition of myoglobin revealed by inelastic neutron scattering, W. Doster, W. Petry and S. Cusack, Nature 337,754(1989)
Comment Doster

Internal dynamics of globular proteins, comparison of neutron scattering measurements and theoretical models by J. Smith, K. Kuczera, B. Tidor, W. Doster, S.Cusack and M. Karplus, Physica B(1989) 156, 437.
Comment Doster

1982: Ligand Binding to Hexokinase
Inelastic neutron scattering analysis of hexokinase dynamics and its modification on binding of glucose by B. Jacrot, S. Cusack, A. Dianoux and D. Engelman, Nature 300 (1982)84
Comment Doster

1980/1996: spurious oscillations of hydration water jump rate
Molecular dynamics of hydrated proteins, H. Middendorf, J. Randall and A. J. Leadbetter, Phil. Trans. R. Soc. Lond.B. (1980) 290, 639. and Middendorf, Phys. B. 226, 113 (1996)
Comment Doster


last changes: June 5th, 2019