OpenNucleome for high resolution nuclear structural and dynamical modeling

Reviewer #1 (Public Review):

Summary:
In this paper, the authors develop a comprehensive program to investigate the organization of chromosome structures at 100 kb resolution. It is extremely well executed. The authors have thought through all aspects of the problem. The resulting software will be most useful to the community. Interestingly they capture many experimental observations accurately. I have very few complaints.

Strengths:
A lot of details are provided. The success of the method is well illustrated. Software is easily available,

Weaknesses:
The number of parameters in the energy function is very large. Is there any justification for this? Could they simplify the functions?

What would the modification be if the resolution is increased?

They should state that the extracted physical values are scale-dependent. For example, viscosity.

Reviewer #2 (Public Review):

Summary:
In this work, Lao et al. develop an open-source software (OpenNucleome) for GPU-accelerated molecular dynamics simulation of the human nucleus accounting for chromatin, nucleoli, nuclear speckles, etc. Using this, the authors investigate the steady-state organization and dynamics of many of the nuclear components.

Strengths:
This is a comprehensive open-source tool to study several aspects of the nucleus, including chromatin organization, interactions with lamins and organization, and interactions with nuclear speckles and nucleoli. The model is built carefully, accounting for several important factors and optimizing the parameters iteratively to achieve experimentally known results. The authors have simulated the entire genome at 100kb resolution (which is a very good resolution to simulate and study the entire diploid genome) and predict several static quantities such as the radius of gyration and radial positions of all chromosomes, and time-dependent quantities like the mean-square displacement of important genomic regions.

Weaknesses:
One weakness of the model is that it has several parameters. Some of them are constrained by the experiments. However, the role of every parameter is not clear in the manuscript.

Reviewer #3 (Public Review):

Summary:
The authors of this study aim to develop OpenNucleome, a computational tool designed to simulate the structure and dynamics of the human nucleus. This software models nuclear components like chromosomes and nuclear bodies, leveraging GPU acceleration for improved performance. The key objective is to enhance our understanding of nuclear organization, providing a tool that aligns with experimental data and is accessible to the genome architecture scientific community.

Strengths:
OpenNucleome offers a detailed and dynamic model of the nucleus, a significant step forward in computational biology.

The integration of GPU acceleration with the OpenMM package is a good technical advancement, potentially enhancing performance.

The comparison with experimental data adds credibility to the tool's accuracy and relevance.

Weaknesses:
The lack of comprehensive tutorials and clear documentation on the OpenNucleome GitHub page is a considerable barrier to accessibility and user-friendliness.

The process for generating necessary input files is not adequately explained, which could hinder the tool's practical application.

The paper could benefit from more explicit explanations on the standardization of practices and cross-validation with existing tools like OpenMiChroM.