Intrinsically disordered protein‐specific force field CHARMM36IDPSFF

Abstract

Intrinsically disordered proteins (IDPs) are closely related to various human diseases. Because IDPs lack certain tertiary structure, it is difficult to use X-ray and NMR methods to measure their structures. Therefore, molecular dynamics simulation is a useful tool to study the conformer distribution of IDPs. However, most generic protein force fields were found to be insufficient in simulations of IDPs. Here, we report our development for the CHARMM community. Our residue-specific IDP force field (CHARMM36IDPSFF) was developed based on the base generic force field with CMAP corrections for all 20 naturally occurring amino acids. Multiple tests show that the simulated chemical shifts with the newly developed force field are in quantitative agreement with NMR experiment and are more accurate than the base generic force field. Comparison of J-couplings with previous work shows that CHARMM36IDPSFF and its corresponding base generic force field have their own advantages. In addition, CHARMM36IDPSFF simulations also agree with experiment for SAXS profiles and radii of gyration of IDPs. Detailed analysis shows that CHARMM36IDPSFF can sample more diverse and disordered conformers. These findings confirm that the newly developed force field can improve the balance of accuracy and efficiency for the conformer sampling of IDPs.

Extensive tests and evaluation of the CHARMM36IDPSFF force field for intrinsically disordered proteins and folded proteins

“…In previous work, we simulated several disordered proteins with C36IDPSFF and the results proved the effectiveness of this force field for IDPs. 21 To further evaluate the force field, six typical disordered proteins were tested in this study, including Amyloid β(1-40) 46 We also calculated the chemical shifts and scalar couplings for other disordered proteins. The results are shown in Fig.…”

“…: Interestingly, we found that the C36IDPSFF force field also performs well for folded proteins in the previous simulation with ubiquitin even though the initial optimized targets are not the folded proteins. 21 In this study, we tested three typical folded proteins from the benchmark set in the previous work by Paul Robustelli et al, 54 including the bovine pancreatic trypsin inhibitor (BPTI), the third IgG-binding domain of protein G (GB3), and hen egg white lysozyme (HEWL), and another three folded proteins (PDB IDs: 2JPU, 2JQN and 2KL6) with more than 100 residues from the set by Mao et al 55 Fig . 5 shows the results of simulations for three typical folded proteins.…”

“…Based on the methods of previous studies, we developed an IDP-specific force field CHARMM36IDPSFF (C36IDPSFF) originating from the CHARMM36m (C36m) force field 20 with modifications of the backbone dihedral correlation map (CMAP) parameters for all 20 amino acids. 21 We reduced the energy barrier between PPII and the right-handed a-helix region in the Ramachandran plot of the previous C36m. This will facilitate conformational conversion and will save a lot of computing resources in achieving enough sampling of IDPs.…”

Catalytic mechanism of butane anaerobic oxidation for alkyl‐coenzyme M reductase

“…The root‐mean‐square deviations (RMSDs), root‐mean‐square fluctuation (RMSF), the distance between two residues, and hydrophobic interaction between substrate and ACR were calculated with the cpptraj module in AmberTools 18 and in‐house software (Chen, 2008, 2009; Chen et al., 2010; Li et al., 2019; Liu et al., 2018, 2019; Qin et al., 2009, 2011; Rahman et al., 2020; Song et al., 2020; Song, Luo, et al., 2017; Song, Wang, et al., 2017; Wang et al., 2013, 2014; Yang et al., 2019; Ye et al., 2015; Yu et al., 2013; Zhang et al., 2019).…”

Development of Charge-Augmented Three-Point Water Model (CAIPi3P) for Accurate Simulations of Intrinsically Disordered Proteins

“…Discrepancies between theory and experiments are commonly attributed to either force field biases [ 2 , 3 ] or insufficient sampling. This motivated the development of molecular force fields designed to handle IDPs [ 4 , 5 , 6 ] and to apply enhanced sampling techniques [ 7 , 8 , 9 , 10 , 11 ] or restraints derived from experimental data (e.g., solution NMR) in simulations of IDPs [ 10 , 12 , 13 ]. The outcomes of those efforts were successful to various extents; however, IDP simulations still require parameter improvements [ 10 , 14 , 15 , 16 , 17 ]…”