Incoherent quasi-elastic neutron scattering (QENS) has been used to measure the dynamics of water molecules in solutions of a model protein backbone, N-acetyl-glycine-methylamide (NAGMA), as a function of concentration, for comparison with results for water dynamics in aqueous solutions of the N-acetyl-leucine-methylamide (NALMA) hydrophobic peptide at comparable concentrations. From the analysis of the elastic incoherent structure factor, we find significant fractions of elastic intensity at high and low concentrations for both solutes, which corresponds to a greater population of protons with rotational time scales outside the experimental resolution (>13 ps). The higherconcentration solutions show a component of the elastic fraction that we propose is due to water motions that are strongly coupled to the solute motions, while for lowconcentration solutions an additional component is activated due to dynamic coupling between inner and outer hydration layers. An important difference between the solute types at the highest concentration studied is found from stretched exponential fits to their experimental intermediate scattering functions, showing more pronounced anomalous diffusion signatures for NALMA, including a smaller stretched exponent β and a longer structural relaxation time τ than those found for NAGMA. The more normal water diffusion exhibited near the hydrophilic NAGMA provides experimental support for an explanation of the origin of the anomalous diffusion behavior of NALMA as arising from frustrated interactions between water molecules when a chemical interface is formed upon addition of a hydrophobic side chain, inducing spatial heterogeneity in the hydration dynamics in the two types of regions of the NALMA peptide. We place our QENS measurements on model biological solutes in the context of other spectroscopic techniques and provide both confirming as well as complementary dynamic information that attempts to give a unifying molecular view of hydration dynamics signatures near peptides and proteins.

We performed classical molecular dynamics simulations using both fixed-charge and polarizable water and protein force fields to contrast the hydration dynamics near hydrophilic and amphiphilic peptides as a function of temperature. The high peptide concentrations we use serve as a model for the surface of folded proteins where hydration layers around each residue overlap significantly. Through simulation we determine that there are notable differences in the water dynamics analyzed from the outer and inner hydration layer regions of the amphiphilic peptide solution that explains the experimentally observed presence of two translational relaxations, while the hydrophilic peptide solution shows only a single non-Arrhenius translational process with no distinction between hydration layers. Given that water dynamics for the amphiphilic peptide system reproduces all known rotational and translational hydration dynamical anomalies exhibited by hydration water near protein surfaces, our analysis provides strong evidence that dynamical signatures near biological interfaces arises because of frustration in the hydration dynamics induced by chemical heterogeneity, as opposed to just topological roughness, of the protein surface.

We present new quasi-elastic neutron scattering experiments and simulation analysis for studying the hydration water dynamics of N-acetyl-leucine-methylamide (NALMA) solutions as a function of concentration and temperature. The experiments show non-Arrhenius translational dynamics over the temperature range of -3 to +37 °C for all concentrations, and fits to the experimental intermediate scattering function show nonexponential relaxation dynamics. While the lower-concentration NALMA solution could be classified as an intermediate to strong liquid, the higher concentration is legitimately defined as a fragile liquid, and the hydration dynamics of the most concentrated solution exhibits very good correspondence with the same signatures of non-Arrhenius behavior and nonexponential dynamics as that observed for supercooled water well below -20 °C. The corresponding molecular dynamics simulation analysis of the high concentration data using the SPC water model, a common companion water model used in protein simulations, is severely limited in application to the dynamics of this system because of the very low temperature of maximum density of the SPC water model. However, the simulations are informative in the sense that nonexponential relaxation is still evident at the effectively higher temperatures, which indicates that the underlying potential energy surface is very rough at high concentrations, although the sampling is still sufficiently ergodic so that Arrhenius behavior is observed. We provide discussion in regards to the mutually beneficial connection between supercooled liquids and glasses and its biological importance for protein-water systems.

We report on molecular dynamics simulations of the frequency-dependent dielectric relaxation spectra at room temperature for aqueous solutions of a hydrophilic peptide and an amphiphilic peptide at two concentrations. We find that only the high-concentration amphiphilic peptide solution exhibits an anomalous dielectric increment over that of pure water, while the hydrophilic peptide exhibits a significant dielectric decrement. The dielectric component analysis carried out by decomposing these peptide solutions into peptide, hydration layer, and outer layer(s) of water clearly shows the presence of a unique dipolar component with a relaxation time scale on the order of approximately 25 ps (compared to the bulk water time scale of approximately 11 ps) that originates from the interaction between the hydration layer water and the outer layer(s) of water. Results obtained from the dielectric component analysis further show the emergence of a distinct and much lower frequency relaxation process for the high-concentration amphiphilic peptide compared to the hydrophilic peptide due to strong peptide dipolar couplings to all constituents, accompanied by a slowing of the structural relaxation in all water layers, giving rise to time scales close to approximately 1 ns. We suggest that the molecular origin of the dielectric relaxation anomalies is due to frustration in the water network arising from the amphiphilic chemistry of the peptide that does not allow it to reorient on the picosecond time scale of bulk water motions. This explanation is consistent with the idea of the "slaving" of residue side chain motions to protein surface water, and furthermore offers the possibility that the anomalous dynamics observed from a number of spectroscopies arises at the interface of hydrophobic and hydrophilic domains on the protein surface.

We report quasi-elastic neutron scattering experiments to contrast the water dynamics as a function of temperature for hydrophilic and amphiphilic peptides under the same level of confinement, as models for understanding hydration dynamics near chemically heterogeneous protein surfaces. We find that the hydrophilic peptide shows only a single non-Arrhenius translational process with no evidence of spatial heterogeneity unlike the amphiphilic peptide solution that exhibits two translational relaxations with an Arrhenius and non-Arrhenius dependence on temperature. Together these results provide experimental proof that heterogeneous dynamical signatures near protein surfaces arise in part from chemical heterogeneity (energy disorder) as opposed to mere topological roughness of the protein surface.

We have conducted extensive molecular dynamics simulations to study the single particle and collective dynamics of water in solutions of N-acetyl-glycine-methylamide, a model hydrophilic protein backbone, and N-acetyl-leucine-methylamide, a model (amphiphilic) hydrophobic peptide, as a function of peptide concentration. Various analytical models commonly used in the analysis of incoherent quasielastic neutron scattering (QENS), are tested against the translational and rotational intermediate scattering function, the mean square displacement of the water molecule center of mass, and fits to the second-order rotational correlation function of water evaluated directly from the simulation data. We find that while the agreement between the model-free analysis and analytical QENS models is quantitatively poor, the qualitative feature of dynamical heterogeneity due to caging is captured well by all approaches. The center of mass collective and single particle intermediate scattering functions of water calculated for these peptide solutions show that the crossover from collective to single particle-dominated motions occurs at a higher value of Q for high concentration solutions relative to low concentration because of the greater restriction in movement of water molecules due to confinement. Finally, we have shown that at the same level of confinement of the two peptides, the aqueous amphiphilic amino acid solution shows the strongest deviation between single particle and collective dynamics relative to the hydrophilic amino acid, indicating that chemical heterogeneity induces even greater spatial heterogeneity in the water dynamics.

Molecular dynamics with coarse-grained models is nowadays extensively used to simulate biomolecular systems at large time and size scales, compared to those accessible to all-atom molecular dynamics. In this review article, we describe the physical basis of coarse-grained molecular dynamics, the coarse-grained force fields, the equations of motion and the respective numerical integration algorithms, and selected practical applications of coarse-grained molecular dynamics. We demonstrate that the motion of coarse-grained sites is governed by the potential of mean force and the friction and stochastic forces, resulting from integrating out the secondary degrees of freedom. Consequently, Langevin dynamics is a natural means of describing the motion of a system at the coarse-grained level and the potential of mean force is the physical basis of the coarse-grained force fields. Moreover, the choice of coarse-grained variables and the fact that coarse-grained sites often do not have spherical symmetry implies a non-diagonal inertia tensor. We describe selected coarse-grained models used in molecular dynamics simulations, including the most popular MARTINI model developed by Marrink’s group and the UNICORN model of biological macromolecules developed in our laboratory. We conclude by discussing examples of the application of coarse-grained molecular dynamics to study biologically important processes.

We have carried out extensive molecular dynamics simulations of a supercooled polydisperse Lennard-Jones liquid with large variations in temperature at a fixed pressure. The particles in the system are considered to be polydisperse in both size and mass. The temperature dependence of dynamical properties such as the viscosity (eta) and the self-diffusion coefficients (D(i)) of different size particles is studied. Both viscosity and diffusion coefficients show super-Arrhenius temperature dependence and fit well to the well-known Vogel-Fulcher-Tammann equation. Within the temperature range investigated, the value of Angell's fragility parameter (D approximately 1.4) classifies the present system as a very fragile liquid. The critical temperature for diffusion (T(D(i))(o)) increases with the size of the particles. The critical temperature for viscosity (T(eta)(o)) is larger than that for diffusion, and sizable deviations appear for the smaller size particles, implying a decoupling of translational diffusion from viscosity in deeply supercooled liquids. Indeed, the diffusion shows markedly non-Stokesian behavior at low temperatures where a highly nonlinear dependence on size is observed. An inspection of the trajectories of the particles shows that at low temperatures the motions of both the smallest and largest size particles are discontinuous (jump type). However, the crossover from continuous Brownian to large length hopping motion takes place at shorter time scales for the smaller size particles.