TIP3P Water Research Articles

Dynamical Behavior of the CAT Domain from Cre Recombinase, in the Absence of and with the CIS Interaction of the N Helix

Cre is a tyrosine recombinase that binds to DNA, promoting its scission, recombination, and ligation at specific sequences known as loxP sites. It is formed by two helical domains (CBD and CAT) separated by a flexible linker. It acts by forming a tetramer that is stabilised by the last C-terminal helix (N helix) and a pocket formed in the adjacent subunit (trans interaction). The lack of this helix leads to loss of Cre functions by impeding complex formation; furthermore, in the monomer context, the N helix could interact in cis with its own CAT domain near the DNA binding site, leading to an auto-inhibitory complex. A structural model explaining these results is still lacking.We generate structural models for the CAT domain in the absence of the N helix and for the interaction in cis, starting from crystallographic structures deposited in the PDB database (PDBID 1Q3U): CAT domain (residues 139 to 326) and segment 327 to 341 (N helix). For the cis interaction models, we used the ClusPro server. All-atom molecular dynamics simulations used the charmm36m forcefield, TIP3P water model, 303K and the GROMACS2018 software. Loss of the N helix results in an increase of flexibility in the CAT domain, with a clam-like motion of the trans binding site, while cis models showed that the N helix visits multiple conformations that may affect complex formation.

Short Arginine-Based Peptides As Predictors for the Extended Structure of Polyarginine Sequences in Intrinsically Disordered Proteins

Intrinsically disordered proteins (IDPs) and regions (IDRs) are often rich with charged amino acids. During important biological processes, protein-biomolecule interactions are often driven by one or more charged residues within an IDR. Several lines of experimental and computational evidence suggest that polypeptides and proteins that carry high net charges tend to adopt extended conformations. Furthermore, the average end to end distances often exceed expectations for self-avoiding random coils. Here, we show that charged arginine (R) residues in even short glycine (G) capped model peptides (GRRG and GRRRG) significantly affect the conformational propensities of each other when compared to the intrinsic propensities of a mostly unperturbed arginine in the tripeptide GRG. A conformational analysis based on experimentally determined J-coupling constants from heteronuclear NMR spectroscopy and amide I’ band profiles from polarized Raman spectroscopy reveals that nearest neighbor interactions stabilize extended β-strand conformations at the expense of polyproline II and turn conformations. The results from MD simulations with an CHARMM36m force field and TIP3P water reproduce our results only to a limited extent. The use of the Ramachandran distribution of the central residue of GRRRG in a calculation of end-to-end distances of polyarginines of different length yielded the expected power law behavior. The scaling coefficient of 0.66 suggests that such peptides would be more extended than predicted by a self-avoiding random walk.

Determination of van der Waals Parameters Using a Double Exponential Potential for Nonbonded Divalent Metal Cations in TIP3P Solvent.

A double exponential (DE) functional form for Lennard-Jones (LJ) interactions, proposed in our previous study, has many advantages over LJ potentials including a natural softcore characteristic for the convenience of the pathway-based free-energy calculations, fast convergence, and flexibility in use. In this work, we put the first step on the application of the DE functional form by identifying a DE potential, coined DE-TIP3P, for molecular simulations using the TIP3P water model. The developed DE-TIP3 potential was better than LJ potential in reproducing the experimental water properties. Afterward, we developed the nonbonded models of 15 divalent metal ions, which frequently appear and play vital roles in biological systems, to be consistent with the DE-TIP3P potential and TIP3P water model. Our nonbonded models were as good as the complicated nonbonded dummy cationic models by Jiang et al. and the nonbonded 12-6-4 LJ models by Li and Merz in reproducing the experimental properties of those ions. Moreover, our nonbonded models achieved a better performance than the compromise (CM) LJ models and 12-6-4 LJ models, developed by Li and Merz, in reproducing the properties of MgCl2 in aqueous solution.

How increasing pressure affects the ion hydration structure and shell properties at ambient temperature

This work deals with the effect of increasing pressure at 298.15 K on the structure and hydration shell properties of ions in infinitely diluted solutions. Results were obtained from NPT Monte Carlo simulations at various pressures, from 1 atm up to 8000 atm, for some alkali metal, alkaline earth and halide ions in TIP4P water. As pressure increases, the ion-O and the ion-H radial distribution functions (rdfs) are subjected to changes to differing extents depending on both the charge and the size of the ion. The first peak of the ion-O rdf is shifted to a shorter distance from the ion for Cs+, Br− and I−, while in the other cases there is no evidence of shortening. In contrast, for the alkaline earth ions, the most prominent effect is the decrease in the height of the first peak. Minima positions of the ion-O rdfs were used to define the first and the second hydration shells at a given pressure. Water dipole orientation with respect to the radial direction was examined, showing that at higher pressures the ion-dipole interaction becomes less attractive than at 1 atm. A much less favorable orientation was found for waters in the first shell of halide ions. Shell properties were computed from definite integrals of the ion-O rdfs, such as the coordination number and the shell contribution to the excess volume. For the first hydration shell, apart from Ca2+, there is a significant increase in the coordination number upon increasing pressure. This effect becomes more important the larger the ion size is and this is very significant for alkali metal and halide ions. In the case of I− the gap observed between 4 katm and 5 katm reflects the striking effect of increasing pressure on the shell definition. The coordination number remains almost constant when using an alternative boundary for the shell. This was suggested by the radial distribution of water-dipole orientations. Shell excess volume contributions are discussed by examining their dependence on pressure. Electrostriction is shown for the first shell, while the second shell's contribution to the excess volume is positive. At a higher pressure, the shell electrostrictive volume per water molecule is always less than at 1 atm. The greatest effect is shown for the first shell of alkaline earth. The effect of a different shell boundary is examined on the shell quantities of halide ions.

Short peptides as predictors for the structure of polyarginine sequences in disordered proteins

Intrinsically disordered proteins and intrinsically disordered regions are frequently enriched in charged amino acids. Intrinsically disordered regions are regularly involved in important biological processes in which one or more charged residues is the driving force behind a protein-biomolecule interaction. Several lines of experimental and computational evidence suggest that polypeptides and proteins that carry high net charges have a high preference for extended conformations with average end-to-end distances exceeding expectations for self-avoiding random coils. Here, we show that charged arginine residues even in short glycine-capped model peptides (GRRG and GRRRG) significantly affect the conformational propensities of each other when compared with the intrinsic propensities of a mostly unperturbed arginine in the tripeptide GRG. A conformational analysis based on experimentally determined J-coupling constants from heteronuclear NMR spectroscopy and amide I′ band profiles from vibrational spectroscopy reveals that nearest-neighbor interactions stabilize extended β-strand conformations at the expense of polyproline II and turn conformations. The results from molecular dynamics simulations with a CHARMM36m force field and TIP3P water reproduce our results only to a limited extent. The use of the Ramachandran distribution of the central residue of GRRRG in a calculation of end-to-end distances of polyarginines of different length yielded the expected power law behavior. The scaling coefficient of 0.66 suggests that such peptides would be more extended than predicted by a self-avoiding random walk. Our findings thus support in principle theoretical predictions.

Implicit Solvation Using the Superposition Approximation (IS-SPA): Extension to Peptides in a Polar Solvent.

Efficient, accurate, and adaptable implicit solvent models remain a significant challenge in the field of molecular simulation. A recent implicit solvent model, IS-SPA, based on approximating the mean solvent force using the superposition approximation, provides a platform to achieve these goals. IS-SPA was originally developed to handle nonpolar solutes in a polar solvent and did not accurately capture polar solvation. Here, we demonstrate that IS-SPA can accurately capture polar solvation by incorporating solvent orientation and accounting for the contributions from long ranged electrostatics. Solvent orientation is approximated as that of an ideal dipole aligned in a mean electrostatic field and an analytic form of the long ranged electrostatics is derived. Parameters for the model are calculated from explicit solvent simulations of an isolated atom or molecule and include atom-based solvent densities, mean electric field functions, radially symmetric averaged Lennard-Jones forces, and multipoles of the explicit solvent model. Using these parameters, IS-SPA accounts for asymmetry of charge solvation and reproduces the explicit solvent potential of mean force of dimerization of two oppositely charged Lennard-Jones spheres in chloroform with high fidelity. Additionally, the model more accurately captures the effect of explicit solvent on the monomer and dimer configurations of alanine dipeptide in chloroform than a generalized Born or constant density dielectric model. The current version of the algorithm is expected to outperform explicit solvent simulations for aggregation of small peptides at concentrations below 150 mM, well above the typical experimental concentrations for these materials.

Effect of the Water Model in Simulations of Protein-Protein Recognition and Association.

We study self-association of ubiquitin and the disordered protein ACTR using the most commonly used water models. We find that dissociation events are found only with TIP4P-EW and TIP4P/2005, while the widely used TIP3P water model produces straightforward aggregation of the molecules due to the absence of dissociation events. We also find that TIP4P/2005 is the only water model that reproduces the fast association/dissociation dynamics of ubiquitin and best identifies its binding surface. Our results show the critical role of the water model in the description of protein–protein interactions and binding.

Assessment of transferable forcefields for protein simulations attests improved description of disordered states and secondary structure propensities, and hints at multi-protein systems as the next challenge for optimization

Continuous assessment of transferable forcefields for molecular simulations is essential to identify their weaknesses and direct improvement efforts. The latest efforts focused on better describing disordered proteins while retaining proper description of folded domains, important because forcefields of the previous generations produce overly compact disordered states. Such improvements should additionally alleviate the related problem of over-stabilized protein–protein interactions, which has been largely overlooked. Here we evaluated three state-of-the-art forcefields, current flagships of their respective developers, optimized for ordered and disordered proteins: CHARMM36m with its recommended corrected TIP3P* water, ff19SB with the recommended OPC water, and the 2019 a99SBdisp forcefield by D. E. Shaw Research with its modified TIP4P water; plus ff14SB with TIP3P as an example of the former generation of forcefields. Our evaluation entailed simulations of (i) multiple copies of a protein that is highly soluble yet undergoes weak dimerization, (ii) a disordered peptide with low, well-characterized alpha helical propensity, and (iii) a peptide known to form insoluble β-aggregates. Our results recapitulate ff14SB-TIP3P over-stabilizing aggregates and secondary structures and place a99SBdisp-TIP4PD at the other end i.e. predicting overly weak intermolecular interactions despite reasonably predicting secondary structure propensities. In-between, CHARMM36m-TIP3P* still over-stabilizes aggregates but predicts residue-wise alpha helical propensities in solution slightly better than ff19SB-OPC, while ff19SB-OPC poses the best prediction of weak dimerization of the soluble protein still predicting aggregation of the β-peptides. This independent assessment shows that the claimed forcefield improvements are real, but also that a right balance between noncovalent attraction and repulsion has not yet been reached. We thus propose developers to consider systems like those tested here in their forcefield tuning protocols. Last, the good performance of CHARMM36m-TIP3P* further shows that tuning 3-point water models might still be an alternative to the more costly 4-point models like OPC and TIP4PD.

Structural and dynamical properties simulations of potassium fluoride aqueous system at various temperatures from 298.15 K to 358.15 K

The energy storage systems are dominated by lithium–ion based chemistry. Currently, the focus has shifted to its nearest neighbours and extensive studies have been carried out on sodium and potassium ion-based batteries. Incorporation of potassium fluoride into solar cells (CIGS) improves the conversion efficiency by increasing the majority carrier concentration. In this study, we present results from molecular dynamics simulations of water solutions and clusters containing potassium fluoride with the interatomic interactions described by OPLS-AA force field for understanding the mechanisms of the physical phenomena of these ionic complexes. The structural and dynamical properties of KF solutions have been studied at various temperatures using TIP4P water model and the ions which are modeled as charged Lennard-Jones particles. The analysis of the simulation results showed that the temperature has decisive effects on the physicochemical properties of the KF electrolyte in aqueous solutions.

Machine learning for reparameterization of four-site water models: TIP4P-BG and TIP4P-BGT.

Parameterizing an effective water model is a challenging issue because of the difficulty in maintaining a comprehensive balance among the diverse physical properties of water with a limited number of parameters. The advancement in machine learning provides a promising path to search for a reliable set of parameters. Based on the TIP4P water model, hence, about 6000 molecular dynamics (MD) simulations for pure water at 1 atm and in the range of 273-373 K are conducted here as the training data. The back-propagation (BP) neural network is then utilized to construct an efficient mapping between the model parameters and four crucial physical properties of water, including the density, vaporization enthalpy, self-diffusion coefficient and viscosity. Without additional time-consuming MD simulations, this mapping operation could result in sufficient and accurate data for high-population genetic algorithm (GA) to optimize the model parameters as much as possible. Based on the proposed parameterizing strategy, TIP4P-BG (a conventional four-site water model) and TIP4P-BGT (an advanced model with temperature-dependent parameters) are established. Both the water models exhibit excellent performance with a reasonable balance among the four crucial physical properties. The relevant mean absolute percentage errors are 3.53% and 3.08%, respectively. Further calculations on the temperature of maximum density, isothermal compressibility, thermal expansion coefficient, radial distribution function and surface tension are also performed and the resulting values are in good agreement with the experimental values. Through this water modeling example, the potential of the proposed data-driven machine learning procedure has been demonstrated for parameterizing a MD-based material model.

Abstract 16069: Molecular Dynamics Simulations Reveal the Functional Impact of Pathogenic Variants in the LDL Receptor LA 4-6 Repeats

Introduction: Functional annotation of rare variants is key to the implementation of genomic medicine. We used molecular dynamics (MD) simulations to assess functional consequences of putative pathogenic variants (PVs) in the low-density lipoprotein receptor gene ( LDLR ). LDLR has a multidomain structure with seven LA repeats and local interactions between these repeats influence ligand binding. However, binding and recycling of the receptor-ligand complex require global changes in conformation. Using MD, we investigated the effects of PVs on long-range dynamics and LDL binding. Methods: An LA 4-6 repeat structure was created from a crystal structure of the extracellular domain (PDB: 1N7D). Structures were solvated with a water box containing TIP3P water molecules and simulated using the AMBER software package with the ff14SB forcefield. The wild type (WT) structure was first relaxed using MD; and subsequently PVs D245Y, F181Y and F181G were modeled. Dynamics were simulated for approximately one microsecond. Values for LDL binding for each PV were obtained from a prior study which used a radioisotope uptake assay. Results: WT domains demonstrated a stable conformation based on root mean square deviation. PVs disrupted the normal distribution in all domains significantly (p < 0.0001), broadening it and introducing multiple peaks. Projection along the top principal components (PCs) showed global destabilization with all PVs. The variant with the greatest impact on LDL binding, F181G, adopted a distinct alternate conformation. Comparison between PV and WT subspaces from PCA correlated with LDL binding (R 2 = 0.99, exponential regression). Structural analysis revealed that the LA5 calcium cage is involved in inter-domain salt bridges, which are disrupted in simulations of PVs. Conclusion: MD simulation of LA4-6 repeats in LDLR suggests PVs alter long-range conformational dynamics, and that such dynamics correlate with LDL binding. The impact of PVs on conformational dynamics and binding may be through disruption of interdomain salt bridges that are mediated by the acidic calcium cage. This study demonstrates the potential utility of MD simulations to functionally characterize LDLR variants.

Molecular dynamics simulations identify the regions of compromised thermostability in SazCA.

The present study examined the structure and dynamics of the most active and thermostable carbonic anhydrase, SazCA, probed using molecular dynamics simulations. The molecular system was described by widely used biological force-fields (AMBER, CHARMM22, CHARMM36, and OPLS-AA) in conjunction with TIP3P water model. The comparison of molecular dynamics simulation results suggested AMBER to be a suitable choice to describe the structure and dynamics of SazCA. In addition to this, we also addressed the effect of temperature on the stability of SazCA. We performed molecular dynamics simulations at 313, 333, 353, 373, and 393 K to study the relationship between thermostability and flexibility in SazCA. The amino acid residues VAL98, ASN99, GLY100, LYS101, GLU145, and HIS207 were identified as the most flexible residues from root-mean-square fluctuations. The salt bridge analysis showed that ion-pairs ASP113-LYS81, ASP115-LYS81, ASP115-LYS114, GLU144-LYS143, and GLU144-LYS206, were responsible for the compromised thermal stability of SazCA.

Influence of Ionic Strength on Hydrophobic Interactions in Water: Dependence on Solute Size and Shape.

Hydrophobicity is a phenomenon of great importance in biology, chemistry, and biochemistry. It is defined as the interaction between nonpolar molecules or groups in water and their low solubility. Hydrophobic interactions affect many processes in water, for example, complexation, surfactant aggregation, and coagulation. These interactions play a pivotal role in the formation and stability of proteins or biological membranes. In the present study, we assessed the effect of ionic strength, solute size, and shape on hydrophobic interactions between pairs of nonpolar particles. Pairs of methane, neopentane, adamantane, fullerene, ethane, propane, butane, hexane, octane, and decane were simulated by molecular dynamics in AMBER 16.0 force field. As a solvent, TIP3P and TIP4PEW water models were used. Potential of mean force (PMF) plots of these dimers were determined at four values of ionic strength, 0, 0.04, 0.08, and 0.40 mol/dm3, to observe its impact on hydrophobic interactions. The characteristic shape of PMFs with three extrema (contact minimum, solvent-separated minimum, and desolvation maximum) was observed for most of the compounds for hydrophobic interactions. Ionic strength affected hydrophobic interactions. We observed a tendency to deepen contact minima with an increase in ionic strength value in the case of spherical and spheroidal molecules. Additionally, two-dimensional distribution functions describing water density and average number of hydrogen bonds between water molecules were calculated in both water models for adamantane and hexane. It was observed that the density of water did not significantly change with the increase in ionic strength, but the average number of hydrogen bonds changed. The latter tendency strongly depends on the water model used for simulations.

Molecular Dynamics Simulations of Channelrhodopsin Chimera, C1C2.

Molecular dynamics (MD) simulations have been successfully used for modeling dynamic behavior of biologically relevant systems, such as ion channels in representative environments to decode protein structure-function relationships. Protocol presented here describes steps for generating input files and modeling a monomer of transmembrane cation channel, channelrhodopsin chimera (C1C2), in representative environment of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) planar lipid bilayer, TIP3P water and ions (Na+ and Cl-) using molecular dynamics package NAMD, molecular graphics/analysis tool VMD, and other relevant tools. MD simulations of C1C2 were performed at 303.15K and in constant particle number, isothermal-isobaric (NpT) ensemble. The results of modeling have helped understand how key interactions in the center of the C1C2 channel contribute to channel gating and subsequent solvent transport across the membrane.

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

Intrinsically disordered proteins (IDPs) are molecules without a fixed tertiary structure, exerting crucial roles in cellular signalling, growth and molecular recognition events. Due to their high plasticity, IDPs are very challenging in experimental and computational structural studies. To provide detailed atomic insight in IDPs’ dynamics governing their functional mechanisms, all-atom molecular dynamics (MD) simulations are widely employed. However, the current generalist force fields and solvent models are unable to generate satisfactory ensembles for IDPs when compared to existing experimental data. In this work, we present a new solvation model, denoted as the Charge-Augmented Three-Point Water Model for Intrinsically Disordered Proteins (CAIPi3P). CAIPi3P has been generated by performing a systematic scan of atomic partial charges assigned to the widely popular molecular scaffold of the three-point TIP3P water model. We found that explicit solvent MD simulations employing CAIPi3P solvation considerably improved the small-angle X-ray scattering (SAXS) scattering profiles for three different IDPs. Not surprisingly, this improvement was further enhanced by using CAIPi3P water in combination with the protein force field parametrized for IDPs. We also demonstrated the applicability of CAIPi3P to molecular systems containing structured as well as intrinsically disordered regions/domains. Our results highlight the crucial importance of solvent effects for generating molecular ensembles of IDPs which reproduce the experimental data available. Hence, we conclude that our newly developed CAIPi3P solvation model is a valuable tool for molecular simulations of intrinsically disordered proteins and assessing their molecular dynamics.

Role of Thermolysin in Catalytic-Controlled Self-Assembly of Fmoc-Dipeptides

In recent years, short peptide self-assembled materials, prepared under the control of the thermolysin catalyst, have been investigated extensively and shown to acquire various morphologies and fun...

Interfacial Water Structure at Zwitterionic Membrane/Water Interface: The Importance of Interactions between Water and Lipid Carbonyl Groups.

In this work, atomistic molecular dynamics (MD) simulations of palmitoyl-oleoyl-phosphatidylcholine (POPC) bilayer were carried out to investigate the effect of water models on membrane dipole potential, which is primarily associated with the preferential orientation of molecular dipoles at the membrane–water interface. We discovered that the overestimation of the dipole potential by the TIPS3P water model can be effectively reduced by the TIP4P water model. On the one hand, the TIP4P water model decreases the negative contribution of lipid to the dipole potential through influencing the orientation of lipid headgroups. On the other hand, the TIP4P water model reduces the positive contribution of water to the dipole potential by increasing the preference of H-down orientation (the water dipole orients toward the bilayer center). Interestingly, the TIP4P water model affects the orientation of interfacial water molecules more obviously than that of lipid headgroups, leading to the decrease in the dipole potential. Furthermore, the MD results revealed that the water close to the positively charged choline (namely, N-associated water) prefers the H-down orientation while the water around the negatively charged phosphate (namely, P-associated water) favors the H-up orientation, in support of recent experimental and MD studies. However, interfacial water molecules are more strongly influenced by the phosphate groups than by the choline groups, resulting in the net H-up orientation (the water dipole orients toward the bilayer center) in the region of lipid headgroups. In addition, it is intriguing that the preference of H-up orientation decreases when water molecules penetrate more deeply into the lipid bilayer. This is attributed to the counteracting effect of lipid carbonyl groups, and the effect varies with the lipid chains (oleoyl and palmitoyl chains), suggesting the important role of lipid carbonyl groups.

Performance of CHARMM36m with modified water model in simulating intrinsically disordered proteins: a case study

Molecular dynamics simulations can be a powerful tool to complement experiments in the study of the structures and dynamics of intrinsically disordered proteins. Though the accuracy of the physics-based all-atom force fields has improved significantly in simulating structured proteins over the past twenty years, most of these force fields face a big challenge to simulate flexible proteins. Recently, CHARMM36m with modified TIP3P model was proposed as a possible solution to simulate intrinsically disordered proteins. Here, we tested the proposed solution using an extensively studied protein, namely NCBD, to explore the performance of CHARMM36m plus modified TIP3P water. Our results suggest that the modified TIP3P water model does enhance the sampling of conformational space compared to the standard TIP3P water model. However, the new CHARMM36m force field still leads to over-compact structures and over-stabilized helices.

4096 Refined structure of human ferroportin using restraints from mass spectrometry

OBJECTIVES/GOALS: Mammals require iron for hemoglobin, respiration, immunity and as cofactor in enzymes. But free iron is toxic from the production of reactive oxygen species. Ferroportin is the sole exporter of cellular iron and it crucially determines cellular and systemic iron levels. Labile iron must be tightly regulated. This requires structural understanding. METHODS/STUDY POPULATION: We built structure of human ferroportin (FPN1) using the ab ignition prediction approaches of Rosetta/Robetta and by comparative modeling with distance restraints in MODELLER. Templates selected were from solute carrier protein families of distantly related orthologs and homologs including a proton coupled peptide transporter (PDB ID: 4IKV) and the bacterial iron transporter in outward-open and inward-open states, (PDB ID: 5AYM, 5AYO). Each model was validated by experimental mass spectrometry data. The energy minimized structural model was inserted into a lipid bilayer, placed in a rectangular simulation box, covered with TIP3P water solvent balanced with counterions and conditioned. Finally, we carried out 350 nanoseconds molecular dynamics simulations. RESULTS/ANTICIPATED RESULTS: Our first model of FPN1 (571aa), using Rosetta/Robetta ab initio approach, resembles the structure of the proton-dependent transporter, POT and consists of 12 transmembrane helices. The membrane spanning helices veer away from the orientation in the structure of 4IKV. The alternate model using MODELLER and the method of satisfaction of constraints, returned one template, the structure of Bdellovibrio bacteriovorus iron (Fe2+) transporter homolog (5AYN, 440aa) with sequence identity of 19%. Aligning FPN1 on the template sequence incorporating structural information revealed better conservation (29%). This model also comprises 12 transmembrane helices in two bundles separated by a large intracellular loop. The iron binding site predicted in both models match the structures of distant bacterial homologs. DISCUSSION/SIGNIFICANCE OF IMPACT: We are using these experimentally verified structures and functional data to answer questions about the mechanism of ferroportin iron transport, structural dynamics and the significance of mutations in ferroportin seen in different populations, especially the Q248H mutation found in Africans and black Americans with moderate to high prevalence.

The accuracy of force fields on the simulation of intrinsically disordered proteins: A benchmark test on the human p53 tumor suppressor

Intrinsically disordered proteins (IDPs) are a class of proteins without stable three-dimensional structures under physiological conditions. IDPs exhibit high dynamic nature and could be described by structural ensembles. As one of the most widely used tools, molecular dynamics (MD) simulation could provide the atomic descriptions of the structural ensemble of IDPs. However, the accuracy of the MD simulation largely depends on the accuracy of the force field. In this paper, we compared the structural ensembles of the activation domain 1 (AD1) in p53 tumor suppressor obtained from the widely used force fields, AMBER99SB-ILDN, CHARMM27, CHARMM36m with different water models. The results show that CHARMM36m generates more extended conformations than other force fields, while CHARMM27 prefers to sample the [Formula: see text]-helical structure. Moreover, the chemical shifts obtained by CHARMM36m are the closest to the experimental measurements. These results indicate that the CHARMM36m force field performs best in characterizing the structure properties of p53 AD1. Water models are also critical to describe the structural ensemble of IDPs. TIP4P water model can obtain more extended conformations and produce more local helical conformations than the TIP3P model in our simulation. In addition, we also compare the chemical shifts predicted by different chemical shift predicting programs with experimental measurements, the results show that SHIFTX2 obtains the best performance in the chemical shifts prediction.