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FakeRotLib: expedient non-canonical amino acid parameterization in Rosetta

Bell, E. W.; Brown, B. P.; Meiler, J.

2025-03-03 bioinformatics
10.1101/2025.02.27.640629 bioRxiv
Show abstract

Non canonical amino acids (NCAAs) occupy an important place, both in natural biology and synthetic applications. However, modeling these amino acids still lies outside the capabilities of most deep learning methods due to sparse training datasets for this task. Instead, biophysical methods such as Rosetta can excel in modeling NCAAs. We discuss the various aspects of parameterizing a NCAA for use in Rosetta, identifying rotamer distribution modeling as one of the most impactful factors of NCAA parameterization on Rosetta performance. To this end, we also present FakeRotLib, a method which uses statistical fitting of small molecule conformer to create rotamer distributions. We find that FakeRotLib outperforms existing methods in a fraction of the time and is able to parameterize NCAA types previously unmodeled by Rosetta.

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