Electrostatic Energetics Research Articles

P176S Mutation Rewires Electrostatic Interactions That Alter Maspin Functionality.

Maspin is known to regress tumors by inhibiting angiogenesis; however, its roles have been reported to be context- and sequence-dependent. Various proteins and cofactors bind to maspin, possibly explaining its conflicting roles. Moreover, polymorphic forms of maspin have also been linked to tumor regression and survival; for instance, maspin with Ser at 176 (maspin-S176) promotes tumors, while maspin with Pro at 176 (maspin-P176) has opposing roles in cancer pathogenesis. With the help of long molecular dynamics simulations, a possible link between polymorphic forms and tumor progression has been established. First, maspin is dynamically stable with either amino acid at the 176 position. Second, differential contacts have been observed among various regions; third, these contacts have significantly altered the electrostatic energetics of various residues; finally, these altered electrostatics of maspin-S176 and maspin-P176 rewire the polar contacts that abolished the allosteric control of the protein. By combining these factors, the altered electrostatics substantially affect the localization and preference of maspin-binding partners, thus culminating in a different maspin-protein(cofactor)-interaction landscape that may have been manifested in previous conflicting reports. Here, the underlying reason has been highlighted and discussed, which may be helpful for better therapeutic manipulation.

Electrostatic Energetics of Bacillus subtilis Ribonuclease P Protein Determined by Nuclear Magnetic Resonance-Based Histidine pKa Measurements.

The pKa values of ionizable groups in proteins report the free energy of site-specific proton binding and provide a direct means of studying pH-dependent stability. We measured histidine pKa values (H3, H22, and H105) in the unfolded (U), intermediate (I), and sulfate-bound folded (F) states of RNase P protein, using an efficient and accurate nuclear magnetic resonance-monitored titration approach that utilizes internal reference compounds and a parametric fitting method. The three histidines in the sulfate-bound folded protein have pKa values depressed by 0.21 ± 0.01, 0.49 ± 0.01, and 1.00 ± 0.01 units, respectively, relative to that of the model compound N-acetyl-l-histidine methylamide. In the unliganded and unfolded protein, the pKa values are depressed relative to that of the model compound by 0.73 ± 0.02, 0.45 ± 0.02, and 0.68 ± 0.02 units, respectively. Above pH 5.5, H22 displays a separate resonance, which we have assigned to I, whose apparent pKa value is depressed by 1.03 ± 0.25 units, which is ∼0.5 units more than in either U or F. The depressed pKa values we observe are consistent with repulsive interactions between protonated histidine side chains and the net positive charge of the protein. However, the pKa differences between F and U are small for all three histidines, and they have little ionic strength dependence in F. Taken together, these observations suggest that unfavorable electrostatics alone do not account for the fact that RNase P protein is intrinsically unfolded in the absence of ligand. Multiple factors encoded in the P protein sequence account for its IUP property, which may play an important role in its function.

Competitive adsorption and ordered packing of counterions near highly charged surfaces: From mean-field theory to Monte Carlo simulations

Competitive adsorption of counterions of multiple species to charged surfaces is studied by a size-effect-included mean-field theory and Monte Carlo (MC) simulations. The mean-field electrostatic free-energy functional of ionic concentrations, constrained by Poisson's equation, is numerically minimized by an augmented Lagrangian multiplier method. Unrestricted primitive models and canonical ensemble MC simulations with the Metropolis criterion are used to predict the ionic distributions around a charged surface. It is found that, for a low surface charge density, the adsorption of ions with a higher valence is preferable, agreeing with existing studies. For a highly charged surface, both the mean-field theory and the MC simulations demonstrate that the counterions bind tightly around the charged surface, resulting in a stratification of counterions of different species. The competition between mixed entropy and electrostatic energetics leads to a compromise that the ionic species with a higher valence-to-volume ratio has a larger probability to form the first layer of stratification. In particular, the MC simulations confirm the crucial role of ionic valence-to-volume ratios in the competitive adsorption to charged surfaces that had been previously predicted by the mean-field theory. The charge inversion for ionic systems with salt is predicted by the MC simulations but not by the mean-field theory. This work provides a better understanding of competitive adsorption of counterions to charged surfaces and calls for further studies on the ionic size effect with application to large-scale biomolecular modeling.

Calculation of pKa in Proteins with the MM_SCP

The accuracy of the Microenvironment Modulated_Screened Coulomb Potential (MM_SCP)1 to predict pKa values for titratable residues in biological macromolecules is analyzed. This self-consistent approach calculates electrostatic energetics using a modified form of the SCP-continuum solvent model2, which is modulated by the hydrophobicity of the local environment around the titratable group. The analysis has been applied to 345 ionizable groups (Asp, Glu, His, Cys, Tyr, Lys, N- and C-termini) in 59 proteins belonging to multiple structural classes. Among these residues, 82% were predicted with errors < 1 unit), although half of residues with large shifts were correctly predicted (error <1 unit). Further analysis showed that the MM_SCP accounts for the pKa shifts of ionizable groups in hydrophobic microenvironment3 and treats interaction energies very well. Most errors originate from steric clashes or improper handling of certain interaction pairs (e.g., ionic H-bonds). A feature in the MM_SCP was used to identify steric clashes between the titratable residue and other parts of the sequence; after local minimization the calculated pKa improved by half a unit in more than half the cases. Other methods to improve the predictions will be discussed, such as optimizing the H-bond network, or using refined reference pKa values4 which improves the root mean square deviations by at least 0.1 unit for 25 proteins.1. Mehler, E.L. and Guarnieri, F., Biophysics J.,1999. 77: p. 3.2. Hassan, S.A., et al. J. Phys. Chem. B,2000. 104: p. 6478.3. Mehler, E.L., et al. PROTEINS: Stru. Func. Genet.,2002. 48: p. 283.4. Thurlkill, R.L., Grimsley, G.R., Scholtz, J.M., and Pace, C.N., Protein Science,2006. 15 p. 1214.

Multiscale Generalized Born Modeling of Ligand Binding Energies for Virtual Database Screening

Generalized Born (GB) models are widely used to study the electrostatic energetics of solute molecules including proteins. Previous work demonstrates that GB models may produce satisfactory solvation energies if accurate effective Born radii are computed for all atoms. Our previous study showed that a GB model which reproduces the solvation energy may not necessarily be suitable for ligand binding calculations. In this work, we studied binding energetics using the exact GB model, in which Born radii are computed from the Poisson-Boltzmann (PB) equation. Our results showed that accurate Born radii lead to very good agreement between GB and PB in electrostatic calculations for ligand binding. However, recently developed GB models with high Born radii accuracy, when used in large database screening, may suffer from time constraints which make accurate, large-scale Born radii calculations impractical. We therefore present a multiscale GB approach in which atoms are divided into two groups. For atoms in the first group, those few atoms which are most likely to be critical to binding electrostatics, the Born radii are computed accurately at the sacrifice of speed. We propose two alternative approaches for atoms in the second group. The Born radii of these atoms may simply be computed by a fast GB method. Alternatively, the Born radii of these atoms may be computed accurately in the free state, and then, a variational form of a fast GB method may be used to compute the change in Born radii experienced by these atoms during binding. This strategy provides an accuracy advantage while still being fast enough for use in the virtual screening of large databases.

Experimental determination and interpretation of the solubility of corundum in H 2O between 350 and 600°C from 0.5 to 2.2 kbar

Corundum solubility was measured in H2O between 350° and 600°C from 0.5 to 2.2 kbar. The base-10 logarithm of molality of Al in equilibrium with corundum along the 0.5 kbar isobar decreases with increasing temperature from −3.44 at 400°C to −5.52 at 600°C, but at 2.0 kbar the logarithm of molality of Al increases from −3.25 at 400°C to −3.09 at 600°C. Electrostatic energetics appear important in stabilizing the dominate Al species as isotherms of solubility are a linear function of the reciprocal of the dielectric constant of H 2O. These results together with values reported for corundum solubility in KOH solutions (Pascal and Anderson, 1989; Azaroual et al., 1996) are used to constrain the dominant Al species in pure H 2O solutions to Al(OH) 3 0. The base-10 logarithm of the molal equilibrium constants for the reaction: Al(OH) 4 − + H + = Al(OH) 3 0 + H 2O at 2.0 kbar and 400°, 500°, 600°, and 700°C are computed to be 6.33, 5.74, 6.39, and 6.75, respectively. It is argued that KAl(OH) 4 0 is not an important species in KOH aqueous solutions as increasing Al(OH) 4 − plus Al(OH) 3 0 with increasing pH and ionic strength can account for the increased corundum solubility within experimental uncertainty.

A QSAR Study of the Ames Mutagenicity of 1‐(X‐Phenyl)‐3,3‐dialkyltriazenes Using Molecular Potential Energy Fields and Molecular Shape Analysis

AbstractA set of 18 1‐(X‐phenyl)‐3,3‐dialkyltriazenes whose mutagenic potencies have been measured were investigated in terms of their potential energy fields. Molecular shape analysis, MSA, was applied to the potential energy field data and a QSAR established. The MSA descriptor, common overlap steric volume between pairs of molecules, found to be a correlate in a previous study [1] is replaced in this study by what physically appears to be the difference in dispersion binding energy between pairs of molecules. A separate investigation of the interrelationship between molecular dielectric representation and corresponding potential energy field based MSA descriptors was carried out. Single molecule MSA descriptors derived from electrostatic energetics are quite dependent on dielectric form, while corresponding pairwise difference MSA features exhibit only a marginal relationship.