BioISI - Instituto de Biossistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal.
Machine Learning Research, Bayer AG, Müllerstraße 178, 13353 Berlin, Germany.
Nucleic Acids Res. 2024 Jul 5;52(W1):W294-W298. doi: 10.1093/nar/gkae255.
When preparing biomolecular structures for molecular dynamics simulations, pKa calculations are required to provide at least a representative protonation state at a given pH value. Neglecting this step and adopting the reference protonation states of the amino acid residues in water, often leads to wrong electrostatics and nonphysical simulations. Fortunately, several methods have been developed to prepare structures considering the protonation preference of residues in their specific environments (pKa values), and some are even available for online usage. In this work, we present the PypKa server, which allows users to run physics-based, as well as ML-accelerated methods suitable for larger systems, to obtain pKa values, isoelectric points, titration curves, and structures with representative pH-dependent protonation states compatible with commonly used force fields (AMBER, CHARMM, GROMOS). The user may upload a custom structure or submit an identifier code from PBD or UniProtKB. The results for over 200k structures taken from the Protein Data Bank and the AlphaFold DB have been precomputed, and their data can be retrieved without extra calculations. All this information can also be obtained from an application programming interface (API) facilitating its usage and integration into existing pipelines as well as other web services. The web server is available at pypka.org.
在准备生物分子结构进行分子动力学模拟时，需要进行 pKa 计算，以在给定 pH 值下提供至少一种代表性的质子化状态。忽略这一步骤，采用水溶液中氨基酸残基的参考质子化状态，通常会导致错误的静电和非物理模拟。幸运的是，已经开发了几种方法来准备结构，考虑到残基在其特定环境中的质子化偏好（pKa 值），其中一些甚至可在线使用。在这项工作中，我们介绍了 PypKa 服务器，它允许用户运行基于物理的方法，以及适用于更大系统的 ML 加速方法，以获得 pKa 值、等电点、滴定曲线以及具有代表性的 pH 依赖性质子化状态的结构，这些结构与常用力场（AMBER、CHARMM、GROMOS）兼容。用户可以上传自定义结构或提交来自 PBD 或 UniProtKB 的标识符代码。已经预先计算了来自蛋白质数据库 (PDB) 和 AlphaFold DB 的超过 20 万个结构的结果，并且可以在无需额外计算的情况下检索其数据。所有这些信息也可以从应用程序编程接口 (API) 获得，这有助于其使用以及与现有管道和其他 Web 服务的集成。该 Web 服务器可在 pypka.org 上获得。
