MPBuild: An Automated Pipeline for High-Fidelity Membrane Protein Simulation System Construction.

Abstract

Membrane proteins serve as the targets for 50% of FDA-approved drugs, but their dynamic characterization via molecular dynamics simulation is hindered by labor-intensive system preparation. To address this challenge, we developed MPBuild─an automated pipeline integrating structural repair, noncanonical component parametrization, and system assembly. Key innovations include (i) template-guided restoration of wild-type sequences and missing domains, (ii) automated force field generation for complex ligands, and (iii) decomposed PDB outputs enabling minute-scale system rebuilding. Benchmarked across 11 diverse membrane protein systems, MPBuild achieved processing times comparable to those of CHARMM-GUI when structural repair durations were excluded. Case studies validated the biophysical accuracy: Reproduced binding interfaces of GPR68-Gq; accurately captured SSTR2/5 and octreotide interactions, and suggested potential novel motifs that may underlie receptor subtype selectivity. In summary, MPBuild serves as a powerful tool for high-throughput membrane protein drug discovery, offering an end-to-end solution that streamlines the entire process from system preparation to simulation.