With millions of experimental and AI-predicted protein structures now available, and the biosynthetic promise of designer proteins emerging, there is an enormous functional characterization challenge that cannot be addressed by experimental techniques alone. Molecular dynamics (MD) simulations offer functional screening with atomic resolution, yet accessibility remains limited for students and scholars. Existing computational chemistry software presents stark trade-offs whereby powerful tools require extensive expertise and manual effort, or user-friendly programs function as black boxes that obscure critical preparation decisions. Addressing these limitations, we present ProPrep, an interactive workflow manager that guides users through expert-quality MD preparation by showing the “what, why, and how” of each step while automating tedious manual operations. Within a single workspace, ProPrep enables downloading PDB structures, performing homology searches, curating and repairing structural issues, applying mutations, parameterizing and converting non-standard residues to force field-compatible forms, generating topology and coordinate files, and executing simulations with active monitoring of key quantities via ASCII visualizations. A key innovation is ProPrep’s extensible framework for detecting, defining, and transforming redox-active sites for forcefield compatibility. Users interactively explore the structure to identify mono- or polynuclear metal sites, organic cofactors, and redox-active amino acids, then apply site-specific transformations that encode all necessary changes to residue and atom identifiers for the chosen forcefield by selecting among available site-type specific transformer modules. Using ProPrep, a 24-heme trimer model of the microbial cytochrome “nanowire” can be submitted to minimization within 5 minutes of downloading the structure. The entire process is recorded in an interactive session log that can be shared and replayed for reproducibility, making simulation setup a fully transparent process that relies on what was done instead of what was remembered and reported.
Walker et al. (Sun,) studied this question.