Department of Biochemistry, Molecular and Cell Biology, Faculty of Science, University of Zaragoza, 50009 Zaragoza, Spain.
Biocomputation and Complex Systems Physics Institute (BIFI), Joint Unit GBs-CSIC, University of Zaragoza, 50018 Zaragoza, Spain.
J Chem Inf Model. 2023 Dec 25;63(24):7791-7806. doi: 10.1021/acs.jcim.3c01107. Epub 2023 Nov 13.
Despite advances in artificial intelligence methods, protein folding remains in many ways an enigma to be solved. Accurate computation of protein folding energetics could help drive fields such as protein and drug design and genetic interpretation. However, the challenge of calculating the state functions governing protein folding from first-principles remains unaddressed. We present here a simple approach that allows us to accurately calculate the energetics of protein folding. It is based on computing the energy of the folded and unfolded states at different temperatures using molecular dynamics simulations. From this, two essential quantities (Δ and ΔCp) are obtained and used to calculate the conformational stability of the protein (Δ). With this approach, we have successfully calculated the energetics of two- and three-state proteins, representatives of the major structural classes, as well as small stability differences (ΔΔ) due to changes in solution conditions or variations in an amino acid residue.
尽管人工智能方法取得了进步，但蛋白质折叠在很多方面仍然是一个待解决的谜。准确计算蛋白质折叠的能态有助于推动蛋白质和药物设计以及基因解读等领域的发展。然而，从第一性原理计算控制蛋白质折叠的状态函数的挑战仍然没有得到解决。我们在这里提出了一种简单的方法，可以准确地计算蛋白质折叠的能态。它基于使用分子动力学模拟在不同温度下计算折叠态和未折叠态的能量。由此，得到了两个重要的量（Δ 和 ΔCp），并用于计算蛋白质的构象稳定性（Δ）。通过这种方法，我们成功地计算了两种和三种状态的蛋白质的能态，这些蛋白质代表了主要的结构类别，以及由于溶液条件的变化或氨基酸残基的变化而导致的小的稳定性差异（ΔΔ）。
