Research And Development Of Molecular Force Field For Intrinsically Disordered Protein

Proteins, as a carrier, perform a critical function in living organisms.The traditional of protein research is based on“Sequence-Structure-Function” paradigm. There are about27%～41%proteins which lack of stable three-dimensional structure in eukaryoticorganisms. These kind of proteins are functionally indispensable andknown as intrinsically disordered protein (IDPs). So IDPs are a collectionof dynamic structure under physiological conditions and have animportant biological function in cell biology and molecular biology.Therefore, IDPs have become an important research area in modernstructural biology and proteomics, because of these characteristics ofIDPs.Generally, IDPs can form a specific three-dimensional structure uponbinding to other biomolecules. In this process, the structure of IDPstransform from disorder to order so that IDPs can play its vital role inorganisms. However, the widely used force field are mainly applied forcommon3D structure.In this paper, a new force field ff99IDPs was developed based onff99SBildn force field. Here, we added the CMAP term ondisorder-promotion residues which are Alanine, Arginine, Glycine,Glutamine, Serine, Glutamic acid, Lysine and Proline. CMAP isnumerical energy correction which essentially transforms the2D φ/ψclassical energy map to match that of a QM calculated map. Oursimulations show that the CMAP corrected Amber parameter setimproves the φ/ψ distributions of the disorder-promoting residues withrespect to the benchmark data of IDPs, with root mean squared percentage deviation less than0.15%between the simulation and thebenchmark. Two IDPs of p53and MeV NTAIL protein were used tovalidate the feasibility of ff99IDPs on the simulation of IDPs. Wecalculated the secondary chemical shift of p53and MeV NTAIL proteinfrom ff99IDPs and ff99SBildn simulation and the chemical shift of bothsystem from ff99IDPs simulations are in quantitative agreement withthose from reported NMR measurements. The Residue Dipolar Couplings(RDCs) was also calculated for p53protein and the coefficient ofcorrelation between couplings of ff99IDPs simulation and experimentalmeasurements is0.761which is much higher than that betweenff99SBildn simulation and experimental measurements. The implicitsimulation also shows that ff99IDPs has a better performance for IDPsthan ff99SBildn.Besides CMAP term, we also refit the charge of Alanine,Arginine, Glycine, Glutamine, Serine, Glutamic acid, Lysine, Proline,Aspartic acid, Histidine, Methionine, and Threonine. Because thedi-peptides for refitting the charge are constrained to helical and extendedconformation in modern widely used force field. So the charge parameterset can only apply to3D structure proteins. Here we use the RESPmodule in Amber software to refitting the charge parameters.