Wednesday, March 4, 2015

Reviews of PCCP paper

The reviews of my PCCP paper arrived on Feb 25th and I forgot to post them. I have started working on the rebuttal.  Comments welcome.

Reviewer(s)' Comments to Author:
Referee: 1

Comments to the Author
This perspective article discusses the many factors that can make small but important contributions to absolute host-guest binding energies computed with electronic structure methods.  This is a valuable contribution to the literature in that it gathers in one place various aspects of solvation and thermodynamics for binding energies.  There are a number of items that I would like to see addressed before this paper is accepted.
(a) State whether ZPE is included in E_gas or in G_gas,RRHO.  I presume in the former, the latter accounting for only the thermal corrections using RRHO. (however, when I see RRHO, I automatically think it includes ZPE)
(b) Recently, some have advocated calculating the gas-phase thermochemistry at an elevated pressure to simulate the decreased translational freedom encountered in solution. Does this affect the thermal and entropy corrections beyond a simple change in volume?  Is this something that should be encouraged?
(c) For delta G_solv(H+), I find it very risky to compute this directly using explicit solvent molecules.  Better to put the H+ on another molecule of known pKa and use continuum solvation to compute the energy difference.
(d) Other ions:  If the ion concentrations are high (experimentally), is it necessary to consider the effect of ionic strength on the activity in calculating the binding energies? Is this a consideration in the computational simulations as well?
(e) Including more than a few explicit waters in a binding energy calculation can also mess up the entropy term, since the positions of these extra water molecules are not sampled adequately.  However, this should not be a problem if only a few tightly bound waters are included.  It would be good to add a comment.
(f) Minor matters:
Pg 3: The sentence before “Molecular Thermodynamics” seems out of place.  Should it be part of the previous paragraph?
Pg 4: “volume of and ideal gas”
Pg 6: “double-differencing” central difference of double numerical difference?
Pg 6: “better to pretend that the imaginary frequency is real” – a very bad idea if the frequency is small, since the entropy blows up. Maybe better to “pretend” that it is a free rotor, which has a well defined entropy.
Pg 9: “van der Waals interactions with the solvent” -> “van der Waals and dispersion interactions with the solvent” (just so there is no misunderstanding)
Pg 10 - Eq 21 and the sentence after it: V_solv or Delta V_solv? (as in Eq 22 and 23)
Pg 11: “numerical instability”? (is this more a matter of numerical noise due to the discretization of the surface elements of the cavity leading to discontinuities in the PES that are problematic for the optimizer – a number of codes have overcome this problem)
Pg 12: For an interesting paper on thermodynamic cycles and solution phase optimization, see DOI: 10.1039/c4cp04538f)
Pg 15: “if protonations states”
Pg 15 – 19, abstract:  The first person is normally not used in scientific writing

Referee: 2

Comments to the Author
This is a perspective about using QM methods to estimate ligand-binding free energies, using approaches originating from QM-cluster studies of enzyme reactions. The perspective is concentrated on the treatment of multiple conformations and pKa effects, although other effects are also mentioned. It is somewhat surprising that the author has not published a single paper on the subject of the perspective; consequently numerical results are very few and discussion is much concentrated on a few publications of the Grimme group. Still, the subject is of general interest. However, the scope needs to be better defined and all methods and formulae need to much better defined before the paper can be accepted.
1. In general, the author should go through all equations and ensure that all terms are defined.
2. The scope of the perspective must be better defined. QM methods have been used for over 10 years for ligand binding to proteins, typically using MM/PBSA-like approaches (cf. publications and reviews by Merz, Hobza and Ryde, for example). Likewise, the author ignores attempts to using QM post-processing FEP calculations.
3. The introduction should start with a more general discussion of available methods to calculate ligand-binding energies and why QM is needed.
4. Different types of QM methods should be described and it should be explained why the author concentrate on DFT and SQM methods.
5. What is TPSS27 (p.3)
6. HF-3c should be explained
7. “by fitting against ∆∆H_f,gas to ∆E_gas values” does not make sense to me.
8. Regarding the low-frequency vibrations, Grimme uses a scaling function so that there are smooth transition between vibrations and free rotation (making the actual value of the frequency unimportant below ~100 cm-1). Truhlar et al. have used a similar approach (but not for ligand binding).
9. The prime problem with conformations is not to use Eqn. 7 but to find all low-energy conformations, including the global minimum.
10. What is the accuracy of computationally estimated pKa values (i.e. what does “fairly accurately” mean quantitatively)? Is it enough for ligand binding?
11. The meaning of dG_solv(H+) should be explained and in general the difference between upper- and lower-case delta should be clarified.
12. What do the over-bar X and L in Eqns 14 and 16, etc. signify?
13. It should be “van der Waals”.
14. I think the selection of the reference state is primarily determined by what experimental results you want to reproduce.
15. A short description of available CM approaches would be appropriate, referring to Table 1.
I suppose you need to specify the variant of PCM also (IEF or C or what?).
16. COSMO-RS is parametrized for many more levels of theory than BP/TZVP.
17. References to the accuracy of solvation energies should be given. In the SAMPL competitions, appreciably worse results are typically seen.
18. I think problem with converging solution-phase optimizations is a problem special to the implementation in Gaussian. With COSMO in Turbomole, no such problems are ever seen.
19. A recent update to Ho et al. 2010 is PCCP 2015, 17, 2859.
20. Since the author only considers water solvation, he should consider changing “solvation” to “hydration”.
21. What is meant by “(dispersion and free energy contributions to the binding free energy” on p.19.

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