Saturday, January 7, 2017

Reviews of Protein structure refinement using a quantum mechanics-based chemical shielding predictor

I have been remiss in posting reviews of my papers. I received this review on November 11, 2016 of a manuscript I submitted to Chemical Science on September 29, 2016.  The paper was accepted November 17 and has appeared online.

REVIEWER REPORT(S):
Referee: 1

Recommendation: Accept

Comments:
Review of 'Protein Structure Refinement Using a Quantum Mechanics-Based
          Chemical Shielding Predictor'


The authors present a method to refine protein structures with respect to
chemical shifts evaluated by their QM-based ProCS15 method. First applications
to a set of different protein structures showed that small structural changes
lead to a significant reduction of the RMSD.

Empirical methods to predict NMR shifts have shown to be able to deliver
results that correlate well with experimental at almost no computational cost,
in particular in comparison with quantum chemical methods. However, these
methods are also insensitive with respect to structural changes of the
molecular structure. In this work, the authors analyse their empirical ProCS15
method, which is parametrized based on quantum chemical reference calculations,
with respect to structural changes in the molecular geometry. First examples
show that their method has a similar high sensitivity with respect to structure
changes as quantum chemical methods. The results indicate that ProCS15 can
hold a 'predictive power' beyond previous empirical methods, i.e., in
applications to more exotic molecular geometries and conformations.

The manuscript is well written and of appropriate length, and certainly of
great interest for the readers of Chemical Science. The presented applications
have been thoroughly analyzed and results are well outlined for the reader.
Since I've have only a few comments/suggestions, no further revision prior to
publication is necessary. However, I would strongly suggest to consider my
suggestion on the ordering of sections (see below).

Comments:

+ My main point is actually regarding to the order of sections in the
 manuscript.  Since the different methods used are constantly refered to in
 the result-section, I would recommend to first outline the
 theory/computational methodology and then present the results of the
 illustrative calculations on the test systems.

+ In the summary, the authors mention that their method might be used to
 improve the accuracy of QM or QM/MM calculations of NMR chemical shifts.
 It is certainly difficult to judge the quality of the ProCS15-optimized
 structures objectively, i.e., without refering to secondary properties like
 NMR shifts. However, it would be interesting to see the impact of the
 structural changes in quantum chemical calculations.
 This point might be beyond the scope of this work, but is certainly worthwile
 to be considered by the authors as a future project.

+ Just a comment on the DFT-based reference calculations used to parametrize
 the ProCS15 method: It might be worthwile considering the use of the KT2
 functional by Keal and Tozer [JCP 119, 3015 (2003)] and the basis sets
 pcS-x/pcSseg-x by Frank Jensen [JCTC 4, 719 (2008):JCTC 10, 1074 (2014)].
 Both functional and basis sets are optimized for NMR chemical shift
 calculations. A benchmark of those method was done by Flaig et al. [JCTC 10,
 572 (2014)].


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