On the Coupling between the Collective Dynamics of Proteins and Their Hydration Water

Picosecond time scale dynamics of hydrated proteins has been connected with the onset of biological activity as it coincides with solvent–solute hydrogen bond rearrangements and amino acid rotational relaxation time scales. The presence and fluctuations of protein hydration water (PHW) largely influence protein motions that are believed to be slaved to those of the solvent, yet to date, how protein and hydration water dynamics are coupled remains unclear. Here, we provide a significant advance in characterizing this coupling; we present the first full study of both the longitudinal and transverse coherent collective motions in a protein–solvent system. The data show unexpectedly the presence in the water dynamics of collective modes belonging to the protein. The properties of these modes, in particular, their propagation velocities and amplitudes, indicate a strengthening of the interactions and a higher rigidity of the network of solvent molecules close to the protein surface. Accordingly, the present study presents the most compelling and clear evidence of a very strong dynamical coupling between a protein and its hydration water, previously suggested by studies using various experimental techniques

Electrochemical Surface Potential Due to Classical Point Charge Models Drives Anion Adsorption to the Air–Water Interface

We demonstrate that the driving forces for ion adsorption to the air–water interface for point charge models result from both cavitation and a term that is of the form of a negative electrochemical surface potential. We carefully characterize the role of the free energy due to the <i>electrochemical</i> surface potential computed from simple empirical models and its role in ionic adsorption within the context of dielectric continuum theory. Our research suggests that the electrochemical surface potential due to point charge models provides anions with a significant driving force for adsoprtion to the air–water interface. This is contrary to the results of ab initio simulations that indicate that the <i>average electrostatic</i> surface potential should favor the desorption of anions at the air–water interface. The results have profound implications for the studies of ionic distributions in the vicinity of hydrophobic surfaces and proteins

Specific Anion Effects on Na⁺ Adsorption at the Aqueous Solution–Air Interface: MD Simulations, SESSA Calculations, and Photoelectron Spectroscopy Experiments

Specific ion effects of the large halide anions have been shown to moderate anion adsorption to the air–water interface (AWI), but little quantitative attention has been paid to the behavior of alkali cations. Here we investigate the concentration and local distribution of sodium (Na⁺) at the AWI in dilute (<1 M) aqueous solutions of NaCl, NaBr, and NaI using a combination of molecular dynamics (MD) and SESSA simulations, and liquid jet ambient pressure photoelectron spectroscopy measurements. We use SESSA to simulate Na 2p photoelectron intensities on the basis of the atom density profiles obtained from MD simulations, and we compare the simulation results with photoelectron spectroscopy experiments to evaluate the performance of a nonpolarizable force field model versus that of an induced dipole polarizable one. Our results show that the nonpolarizable force model developed by Horinek and co-workers (<i>Chem. Phys. Lett.</i> <b>2009</b>, <i>479</i>, 173–183) accurately predicts the local concentration and distribution of Na⁺ near the AWI for all three electrolytes, whereas the polarizable model does not. To our knowledge, this is the first interface-specific spectroscopic validation of a MD force field. The molecular origins of the unique Na⁺ distributions for the three electrolytes are analyzed on the basis of electrostatic arguments, and shown to arise from an indirect anion effect wherein the identity of the anion affects the strength of the attractive Na⁺–H₂O electrostatic interaction. Finally, we use the photoelectron spectroscopy results to constrain the range of inelastic mean free paths (IMFPs) for the three electrolyte solutions used in the SESSA simulations that are able to reproduce the experimental intensities. Our results suggest that earlier estimates of IMFPs for aqueous solutions are likely too high

Multi-Conformation Monte Carlo: A Method for Introducing Flexibility in Efficient Simulations of Many-Protein Systems

We present a novel multi-conformation Monte Carlo simulation method that enables the modeling of protein–protein interactions and aggregation in crowded protein solutions. This approach is relevant to a molecular-scale description of realistic biological environments, including the cytoplasm and the extracellular matrix, which are characterized by high concentrations of biomolecular solutes (e.g., 300–400 mg/mL for proteins and nucleic acids in the cytoplasm of Escherichia coli). Simulation of such environments necessitates the inclusion of a large number of protein molecules. Therefore, computationally inexpensive methods, such as rigid-body Brownian dynamics (BD) or Monte Carlo simulations, can be particularly useful. However, as we demonstrate herein, the rigid-body representation typically employed in simulations of many-protein systems gives rise to certain artifacts in protein–protein interactions. Our approach allows us to incorporate molecular flexibility in Monte Carlo simulations at low computational cost, thereby eliminating ambiguities arising from structure selection in rigid-body simulations. We benchmark and validate the methodology using simulations of hen egg white lysozyme in solution, a well-studied system for which extensive experimental data, including osmotic second virial coefficients, small-angle scattering structure factors, and multiple structures determined by X-ray and neutron crystallography and solution NMR, as well as rigid-body BD simulation results, are available for comparison

Watching the Low-Frequency Motions in Aqueous Salt Solutions: The Terahertz Vibrational Signatures of Hydrated Ions

The details of ion hydration still raise fundamental questions relevant to a large variety of problems in chemistry and biology. The concept of water “structure breaking” and “structure making” by ions in aqueous solutions has been invoked to explain the Hofmeister series introduced over 100 years ago, which still provides the basis for the interpretation of experimental observations, in particular the stabilization/destabilization of biomolecules. Recent studies, using state-of-the-art experiments and molecular dynamics simulations, either challenge or support some key points of the structure maker/breaker concept, specifically regarding long-ranged ordering/disordering effects. Here, we report a systematic terahertz absorption spectroscopy and molecular dynamics simulation study of a series of aqueous solutions of divalent salts, which adds a new piece to the puzzle. The picture that emerges from the concentration dependence and assignment of the observed absorption features is one of a limited range of ion effects that is confined to the first solvation shell

Direct Evidence of Conformational Changes Associated with Voltage Gating in a Voltage Sensor Protein by Time-Resolved X‑ray/Neutron Interferometry

The voltage sensor domain (VSD) of voltage-gated cation (e.g., Na⁺, K⁺) channels central to neurological signal transmission can function as a distinct module. When linked to an otherwise voltage-insensitive, ion-selective membrane pore, the VSD imparts voltage sensitivity to the channel. Proteins homologous with the VSD have recently been found to function themselves as voltage-gated proton channels or to impart voltage sensitivity to enzymes. Determining the conformational changes associated with voltage gating in the VSD itself in the absence of a pore domain thereby gains importance. We report the direct measurement of changes in the scattering-length density (SLD) profile of the VSD protein, vectorially oriented within a reconstituted phospholipid bilayer membrane, as a function of the transmembrane electric potential by time-resolved X-ray and neutron interferometry. The changes in the experimental SLD profiles for both polarizing and depolarizing potentials with respect to zero potential were found to extend over the entire length of the isolated VSD’s profile structure. The characteristics of the changes observed were in qualitative agreement with molecular dynamics simulations of a related membrane system, suggesting an initial interpretation of these changes in terms of the VSD’s atomic-level 3-D structure

“Bind and Crawl” Association Mechanism of <i>Leishmania major</i> Peroxidase and Cytochrome <i>c</i> Revealed by Brownian and Molecular Dynamics Simulations

<i>Leishmania major</i>, the parasitic causative agent of leishmaniasis, produces a heme peroxidase (LmP), which catalyzes the peroxidation of mitochondrial cytochrome <i>c</i> (LmCytc) for protection from reactive oxygen species produced by the host. The association of LmP and LmCytc, which is known from kinetics measurements to be very fast (∼10⁸ M^–1 s^–1), does not involve major conformational changes and has been suggested to be dominated by electrostatic interactions. We used Brownian dynamics simulations to investigate the mechanism of formation of the LmP–LmCytc complex. Our simulations confirm the importance of electrostatic interactions involving the negatively charged D211 residue at the LmP active site, and reveal a previously unrecognized role in complex formation for negatively charged residues in helix A of LmP. The crystal structure of the D211N mutant of LmP reported herein is essentially identical to that of wild-type LmP, reinforcing the notion that it is the loss of charge at the active site, and not a change in structure, that reduces the association rate of the D211N variant of LmP. The Brownian dynamics simulations further show that complex formation occurs via a “bind and crawl” mechanism, in which LmCytc first docks to a location on helix A that is far from the active site, forming an initial encounter complex, and then moves along helix A to the active site. An atomistic molecular dynamics simulation confirms the helix A binding site, and steady state activity assays and stopped-flow kinetics measurements confirm the role of helix A charges in the association mechanism