General Purpose Water Model Can Improve Atomistic Simulations of Intrinsically Disordered Proteins

Abstract

Unconstrained atomistic simulations of intrinsically disordered proteins and peptides (IDP) remain a challenge: widely used, “general purpose” water models tend to favor overly compact structures relative to experiment. Here we have performed a total of 93 μs of unrestrained MD simulations to explore, in the context of IDPs, a recently developed “general-purpose” 4-point rigid water model OPC, which describes liquid state of water close to experiment. We demonstrate that OPC, together with a popular AMBER force field ff99SB, offers a noticeable improvement over TIP3P in producing more realistic structural ensembles of three common IDPs benchmarks: 55-residue apo N-terminal zinc-binding domain of HIV-1 integrase (“protein IN”), amyloid β-peptide (Aβ42) (residues 1-42), and 26-reside H4 histone tail. As a negative control, computed folding profile of a regular globular miniprotein (CLN025) in OPC water is in appreciably better agreement with experiment than that obtained in TIP3P, which tends to overstabilize the compact native state relative to the extended conformations. We employed Aβ42 peptide to investigate the possible influence of the solvent box size on simulation outcomes. We advocate a cautious approach for simulations of IDPs: we suggest that the solvent box size should be at least four times the radius of gyration of the random coil corresponding to the IDP. The computed free energy landscape of protein IN in OPC resembles a shallow “tub” – conformations with substantially different degrees of compactness that are within 2 k B T of each other. Conformations with very different secondary structure content coexist within 1 k B T of the global free energy minimum. States with higher free energy tend to have less secondary structure. Computed low helical content of the protein has virtually no correlation with its degree of compactness, which calls into question the possibility of using the helicity as a metric for assessing performance of water models for IDPs, when the helicity is low. Predicted radius of gyration ( R g ) of H4 histone tail in OPC water falls in-between that of a typical globular protein and a fully denatured protein of the same size; the predicted R g is consistent with two independent predictions. In contrast, H4 tail in TIP3P water is as compact as the corresponding globular protein. The computed free energy landscape of H4 tail in OPC is relatively flat over a significant range of compactness, which, we argue, is consistent with its biological function as facilitator of internucleosome interactions.

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

“…This shows that both the CAIPi3P and OPC models obtain accurate ensembles for partially disordered macromolecules ( Figure 6 , and Table 2 and Table 3 ) and both models are suitable for simulations for IDPs. This also confirms that the OPC model can accurately sample disordered regions, as shown previously by Shabane and coworkers [ 24 ].…”

“…To start, none of them accurately reproduces the key properties of bulk water [ 23 ]. Alternative approaches, most notably the “optimal” three-charge, four-point rigid water model (OPC) [ 24 ] have been developed and tested recently. OPC uses the optimised distribution of point charges to best describe the electrostatics of the water molecule, in contrast to the ‘conventional’ approach to constructing the classical solvation models, which often imposes geometry constraints [ 25 ].…”

Competitive binding of HIF-1α and CITED2 to the TAZ1 domain of CBP from molecular simulations

“…Here we use molecular simulations to investigate the binding of HIF-1α and CITED2 to the TAZ1 domain of CBP. In the last years there have been remarkable improvements in force fields for explicit solvent, atomistic molecular dynamics (MD), which have been recalibrated to reproduce the properties of IDPs [25][26][27][28] . However, simulating full protein-protein binding with all atom MD simulations is extremely demanding even for binary systems 29,30 .…”

Full structural ensembles of intrinsically disordered proteins from unbiased molecular dynamics simulations

“…Molecular dynamics (MD) simulation can in principle provide the missing information and furnish a complete atomic resolution description of IDP structure and dynamics. 2 Recent optimizations of the protein and water potential energy functions 2,[16][17][18][19][20][21][22][23][24][25][26][27] have led to accurate simulation of short disordered peptides and model systems. 17,18,[28][29][30][31] However, the simulations are agreement with experimental data on both local and global properties when employing either of two force fields (Amber ff03ws 19 with TIP4P/2005s 19 and Amber ff99SB-disp 16 with modified TIP4P-D, 16 hereafter termed as a03ws and a99SB-disp respectively).…”