labarba
commented
3 years ago item 1
The article focuses on a use case of questionable value: the solvation energies of very large macromolecules. While this quantity makes sense as a metric for evaluating accuracy/convergence with respect to mesh discretization, the notion of a "[polar] solvation energy" for a virus is not particularly meaningful. The authors should clarify why this quantity is being used and provide readers with a discussion of how the code is meant to be used for physically meaningful quantities of interest.
The showcase calculation in the paper is meant to illustrate the capacity of our software. We focus on a virus for the case study because of the scale. While structure-based computations, like solvation energy, are more meaningful for small rigid molecules, in the case of large molecules, ensemble computations are valuable: many conformations can be run to obtain an energy landscape. With our workflow running from Jupyter notebook, a researcher may run sets of experiments where short dynamics simulations are coupled with solvation energy calculations, quantifying such variations. This type of approach is widely used, e.g., MMPBSA [1], even for very large molecular structures [2,3]. Another setting where the computational workflow would be useful is computing binding energies of large molecules [4], as long as the binding process does not involve large conformational changes. These are well-known limitations of the PB model. Regardless, the electrostatic (polar) free energy is a useful quantity to analyze virion-scale systems. For example, it has been used to study the structure [5] and stability of the capsid with varying pH [6].
We have added a discussion on the use of our code as part of a computational workflow, and the relevance in large-scale problems, such as viruses, with the corresponding references.
[1] Wang, Changhao, et al. "Recent developments and applications of the MMPBSA method." Frontiers in molecular biosciences 4 (2018): 87. [2] Karim, Hana Atiqah Abdul, et al. "Molecular dynamics simulation on designed antibodies of HIV-1 capsid protein (p24)." 3rd International Conference on Computation for Science and Technology (ICCST-3). Atlantis Press, 2015. [3] Li, Chuan, et al. "Highly efficient and exact method for parallelization of grid‐based algorithms and its implementation in DelPhi." Journal of computational chemistry 33.24 (2012): 1960-1966. [4] Wang, Ercheng, et al. "End-point binding free energy calculation with MM/PBSA and MM/GBSA: strategies and applications in drug design." Chemical reviews 119.16 (2019): 9478-9508. [5] Šiber, Antonio, Anže Lošdorfer Božič, and Rudolf Podgornik. "Energies and pressures in viruses: contribution of nonspecific electrostatic interactions." Physical chemistry chemical physics 14.11 (2012): 3746-3765. [6] Roshal, D., et al. "pH-induced morphological changes of proteinaceous viral shells." Scientific reports 9.1 (2019): 1-9.
- fixed in 296db8cb7408e07dc2187e461093f7150c1c0030 and 9f51eea8f209cf2e7cd377f71b78ff13e70dba19
This is an interesting article that describes a well-engineered, robust/reproducible, and very accessible (Jupyter notebooks) Poisson-Boltzmann solver. The authors have done an excellent job describing the rationale for the software, making it straightforward to install via Conda, and ensuring that the results of the paper are reproducible. Overall, the paper is sound and should be of interest to the journal audience. However, there are several issues that detract from the overall accessibility/impact of the article:
[x] 1. The article focuses on a use case of questionable value: the solvation energies of very large macromolecules. While this quantity makes sense as a metric for evaluating accuracy/convergence with respect to mesh discretization, the notion of a "[polar] solvation energy" for a virus is not particularly meaningful. The authors should clarify why this quantity is being used and provide readers with a discussion of how the code is meant to be used for physically meaningful quantities of interest.
[x] 2. It is unclear who the target audience is for either the paper or the software. The paper spends a significant amount of space discussing issues such as interior/exterior versions of the derivative formulation and eigen-spectra of the operators. This could be interesting to developers of BEM solvers but is unlikely to be meaningful to many consumers of biomolecular electrostatics software.
[x] 3. The discussion of mass matrix preconditioning was difficult to follow. In particular, it was unclear whether inversion of the mass matrix was a necessary step for solution of the problem or a way to improve conditioning. Therefore, it was unclear whether approximation of the matrix led to any issues with accuracy of the solution.
[x] 4. Was Nanoshaper used for all meshes in the paper? This was unclear and is important for generalizing the results of the paper to other molecules.
[x] 5.
/usr/bin/time -vis not a standard option for all flavors of Linux; the authors should clarify.[x] 6. The "Laplace" and "Helmholtz" FMM variants were introduced without sufficient description. Do these refer to the Poisson and linearized Poisson-Boltzmann formulations, respectively? More generally, the paper does a poor job of describing which version of the Poisson-Boltzmann equation it is solving (this isn't introduced until Section 4).
[x] 7. There appears to be a typographical error on page 8: "Richard extrapolation" instead of "Richardson extrapolation".