The Surface Potential of the Water–Vapor Interface from Classical Simulations

The electrochemical surface potential across the water–vapor interface provides a measure of the orientation of water molecules at the interface. However, the large discrepancies between surface potentials calculated from <i>ab initio</i> (AI) and classical molecular dynamics (MD) simulations indicate that what is being calculated may be relevant to different test probes. Although a method for extracting the electrochemical surface potential from AIMD simulations has been given, methods for MD simulations have not been clarified. Here, two methods for extracting the surface potential relevant to electrochemical measurements from MD simulations are presented. This potential is shown to be almost entirely due to the dipole contribution. In addition, the molecular origin of the dipole contribution is explored by using different potential energy functions for water. The results here show that the dipole contribution arises mainly from distortions in the hydration shell of the full hydrogen bonded waters on the liquid side of the interface, which is determined by the charge distribution of the water model. Disturbingly, the potential varies by 0.4 eV depending on the model. Although there is still no consensus on what that charge distribution should be, recent results indicate that it contains both a large quadrupole and negative charge out of the molecular plane, i.e., three-dimensional (3D) charge. Water models with 3D charge give the least distortion of the hydration shell and the best agreement with experimental surface potentials, although there is still uncertainty in the experimental values

Identifying Residues That Cause pH-Dependent Reduction Potentials

The pH dependence of the reduction potential <i>E</i>° for a metalloprotein indicates that the protonation state of at least one residue near the redox site changes and may be important for its activity. The responsible residue is usually identified by site-specific mutagenesis, which may be time-consuming. Here, the titration of <i>E</i>° for <i>Chromatium vinosum</i> high-potential iron–sulfur protein is predicted to be in good agreement with experiment using density functional theory and Poisson–Boltzmann calculations if only the sole histidine undergoes changes in protonation. The implementation of this approach into CHARMMing, a user-friendly web-based portal, allows users to identify residues in other proteins causing similar pH dependence

Understanding Rubredoxin Redox Sites by Density Functional Theory Studies of Analogues

Determining the redox energetics of redox site analogues of metalloproteins is essential in unraveling the various contributions to electron transfer properties of these proteins. Since studies of the [4Fe–4S] analogues show that the energies are dependent on the ligand dihedral angles, broken symmetry density functional theory (BS-DFT) with the B3LYP functional and double-ζ basis sets calculations of optimized geometries and electron detachment energies of [1Fe] rubredoxin analogues are compared to crystal structures and gas-phase photoelectron spectroscopy data, respectively, for [Fe­(SCH₃)₄]^0/1–/2–, [Fe­(S₂-<i>o</i>-xyl)₂]^0/1–/2–, and Na⁺[Fe­(S₂-<i>o</i>-xyl)₂]^1–/2– in different conformations. In particular, the study of Na⁺[Fe­(S₂-<i>o</i>-xyl)₂]^1–/2– is the only direct comparison of calculated and experimental gas phase detachment energies for the 1–/2– couple found in the rubredoxins. These results show that variations in the inner sphere energetics by up to ∼0.4 eV can be caused by differences in the ligand dihedral angles in either or both redox states. Moreover, these results indicate that the protein stabilizes the conformation that favors reduction. In addition, the free energies and reorganization energies of oxidation and reduction as well as electrostatic potential charges are calculated, which can be used as estimates in continuum electrostatic calculations of electron transfer properties of [1Fe] proteins

Effects of Microcomplexity on Hydrophobic Hydration in Amphiphiles

Hydrophobic hydration is critical in biology as well as many industrial processes. Here, computer simulations of ethanol/water mixtures show that a three-stage mechanism of dehydration of ethanol explains the anomalous concentration dependence of the thermodynamic partial molar volumes, as well as recent data from neutron diffraction and Raman scattering. Moreover, the simulations show that the breakdown of hydrophobic hydration shells, whose structure is determined by the unique molecular properties of water, is caused by the microcomplexity of the environment and may be representative of early events in protein folding and structure stabilization in aqueous solutions

Quasiharmonic Analysis of the Energy Landscapes of Dihydrofolate Reductase from Piezophiles and Mesophiles

A quasiharmonic analysis (QHA) method is used to compare the potential energy landscapes of dihydrofolate reductase (DHFR) from a piezophile (pressure-loving organism), <i>Moritella profunda</i> (Mp), and a mesophile, <i>Escherichia coli</i> (Ec). The QHA method considers atomic fluctuations of the protein as motions of an atom in a local effective potential created by neighboring atoms and quantitates it in terms of effective force constants, isothermal compressibilities, and thermal expansivities. The analysis indicates that the underlying potential energy surface of MpDHFR is inherently softer than that of EcDHFR. In addition, on picosecond time scales, the energy surfaces become more similar under the growth conditions of Mp and Ec. On these time scales, DHFR behaves as expected; namely, increasing temperature makes the effective energy minimum less steep because thermal fluctuations increase the available volume, whereas increasing pressure steepens it because compression reduces the available volume. Our longer simulations show that, on nanosecond time scales, increasing temperature has a similar effect as on picosecond time scales because thermal fluctuations increase the volume even more on a longer time scale. However, these simulations also indicate that, on nanosecond time scales, pressure makes the local potential <i>less</i> steep, contrary to picosecond time scales. Further examination of the QHA indicates the nanosecond pressure response may originate at picosecond time scales at the exterior of the protein, which suggests that protein–water interactions may be involved. The results may lead to understanding adaptations in enzymes made by piezophiles that enable them to function at higher pressures

Example of Structure Editing module setup for iron-sulfur containing proteins.

<p>Example of Structure Editing module setup for iron-sulfur containing proteins.</p

Web-Based Computational Chemistry Education with CHARMMing III: Reduction Potentials of Electron Transfer Proteins

<div><p>A module for fast determination of reduction potentials, <i>E°</i>, of redox-active proteins has been implemented in the CHARMM INterface and Graphics (CHARMMing) web portal (<a href="http://www.charmming.org" target="_blank">www.charmming.org</a>). The free energy of reduction, which is proportional to <i>E°</i>, is composed of an intrinsic contribution due to the redox site and an environmental contribution due to the protein and solvent. Here, the intrinsic contribution is selected from a library of pre-calculated density functional theory values for each type of redox site and redox couple, while the environmental contribution is calculated from a crystal structure of the protein using Poisson-Boltzmann continuum electrostatics. An accompanying lesson demonstrates a calculation of <i>E°</i>. In this lesson, an ionizable residue in a [4Fe-4S]-protein that causes a pH-dependent <i>E°</i> is identified, and the <i>E°</i> of a mutant that would test the identification is predicted. This demonstration is valuable to both computational chemistry students and researchers interested in predicting sequence determinants of <i>E°</i> for mutagenesis.</p></div

Assessment of Quantum Mechanical Methods for Copper and Iron Complexes by Photoelectron Spectroscopy

Broken-symmetry density functional theory (BS-DFT) calculations are assessed for redox energetics [Cu­(SCH₃)₂]^1–/0, [Cu­(NCS)₂]^1–/0, [FeCl₄]^1–/0, and [Fe­(SCH₃)₄]^1–/0 against vertical detachment energies (VDE) from valence photoelectron spectroscopy (PES), as a prelude to studies of metalloprotein analogs. The M06 and B3LYP hybrid functionals give VDE that agree with the PES VDE for the Fe complexes, but both underestimate it by ∼400 meV for the Cu complexes; other hybrid functionals give VDEs that are an increasing function of the amount of Hartree–Fock (HF) exchange and so cannot show good agreement for both Cu and Fe complexes. Range-separated (RS) functionals appear to give a better distribution of HF exchange since the negative HOMO energy is approximately equal to the VDEs but also give VDEs dependent on the amount of HF exchange, sometimes leading to ground states with incorrect electron configurations; the LRC-<i>ω</i>PBEh functional reduced to 10% HF exchange at short-range give somewhat better values for both, although still ∼150 meV too low for the Cu complexes and ∼50 meV too high for the Fe complexes. Overall, the results indicate that while HF exchange compensates for self-interaction error in DFT calculations of both Cu and Fe complexes, too much may lead to more sensitivity to nondynamical correlation in the spin-polarized Fe complexes

Example of the graphic interface for making point mutations in CHARMMing.

<p>Example of the graphic interface for making point mutations in CHARMMing.</p

Initial submission form (left) and submission form showing results (right) for the redox module.

<p>Initial submission form (left) and submission form showing results (right) for the redox module.</p