Proteins: A Theoretical Perspective of Dynamics, Structure, and Thermodynamics. C.L. Brooks III, M. Karplus, and B. M. Pettitt.This treatise, published as Vol. LXXI of the Advances in Chemical Physics series, is an enlightening introduction to the new and rapidly developing field of molecular dynamics of proteins. Written in clear language, with relatively few equations and a comprehensive reference list, it discusses methodology and numerical procedures applied, elaborates on the major results obtained to date, and concludes with a comparison between molecular dynamics calculations and experiment. In the methodology section, the authors cover the semiempirical potential energy functions and the variety of dynamical simulation techniques (classical and stochastic trajectories, normal mode analysis, and Monte Carlo energy minimization) as they apply to proteins. The authors are careful to point out both merits and possible pitfalls in the various methods. Results obtained in several groups are logically organized in a hierarchial fashion: From small motions of side chains, through larger backbone motions, to large motions of rigid structures, e.g., double helices and domains. Hence the incredibly complex motions in proteins unfold for longer and longer time scales. The influence of additional solvent molecules on the vacuum simulations is discussed. The qualitative agreement with experiment of such detailed calculations is remarkable. It is noted that the theoretical results actually contain much more information than can conceivably be generated by experiment.Although barely older than one decade, the field of protein dynamics has already changed our concept of proteins dramatically. While the impression given by classical X-ray studies is of rigid, well-defined protein structures which are all-important to their function (i.e., the lock-and-key picture for enzyme-substrate activity), it is becoming increasingly clear from molecular dynamics simulations that protein fluctuations can have relatively large magnitudes and that these play a crucial role in protein activity. This is observed for all length and time scales: The rotation of a

The hydration behavior of two planar nanoscopic hydrophobic solutes in liquid water at normal temperature and pressure is investigated by calculating the potential of mean force between them at constant pressure as a function of the solute-solvent interaction potential. The importance of the effect of weak attractive interactions between the solute atoms and the solvent on the hydration behavior is clearly demonstrated. We focus on the underlying mechanism behind the contrasting results obtained in various recent experimental and computational studies on water near hydrophobic solutes. The length scale where crossover from a solvent separated state to the contact pair state occurs is shown to depend on the solute sizes as well as on details of the solute-solvent interaction. We find the mechanism for attractive mean forces between the plates is very different depending on the nature of the solute-solvent interaction which has implications for the mechanism of the hydrophobic effect for biomolecules.

Hydration sites are high-density regions in the three-dimensional time-averaged solvent structure in molecular dynamics simulations and diffraction experiments. In a simulation of sperm whale myoglobin, we found 294 such high-density regions. Their positions appear to agree reasonably well with the distributions of waters of hydration found in 38 x-ray and 1 neutron high-resolution structures of this protein. The hydration sites are characterized by an average occupancy and a combination of residence time parameters designed to approximate a distribution of residence times. It appears that although the occupancy and residence times of the majority of sites are rather bulk-like, the residence time distribution is shifted toward the longer components, relative to bulk. The sites with particularly long residence times are located only in the cavities and clefts of the protein. This indicates that other factors, such as hydrogen bonds and hydrophobicity of underlying protein residues, play a lesser role in determining the residence times of the longest-lived sites.

Using the specialization of the extended RISM equation to infinitely dilute systems, we have calculated correlation functions and interionic potentials of mean force for a set of models corresponding to the first few alkali halides in water. From the results obtained at infinite dilution we calculate the lowest order corrections to the solution properties of the ions. Higher concentrations are explored by using the interionic potentials of mean force at infinite dilution as effective solvent mediated pair potentials. Our results indicate that certain thermodynamic properties, such as the mean activity coefficients and osmotic pressures, are quite sensitive to the details of both the theory and the potential models.

Many theoretical, computational, and experimental techniques recently have been successfully used for description of the solvent distribution around macromolecules. In this Account, we consider recent developments in the areas of protein and nucleic acid solvation and hydration as seen by experiment, theory, and simulations. We find that in most cases not only the general phenomena of solvation but even local hydration patterns are more accurately discussed in the context of water distributions rather than individual molecules of water. While a few localized or high-residency waters are often associated with macromolecules in solution (or crystals from aqueous liquors), these are readily and accurately included in this more general description. The goal of this Account is to review the theoretical models used for the description of the interfacial solvent structure on the border near DNA and protein molecules. In particular, we hope to highlight the progress in this field over the past five years with a focus on comparison of simulation and experimental results.

The solvent structure and dynamics around myoglobin is investigated at the microscopic level of detail by computer simulation. We analyze a molecular dynamics trajectory in terms of solvent mobility and probability distribution. Local events, occurring in the protein-solvent interfacial region, which are often masked by other approaches are thus revealed. Specifically, the local solvent mobility is greatly enhanced for certain locations at the protein surface and in its interior. In addition, a strong correlation between the solvent mobility and density emerges on both global and local scales. We propose a simple model where the solvent distribution measured perpendicularly to the protein surface is utilized to reconstruct the simulated network of hydration within 6 A from the protein surface with a relative error of only 17%. The global precision of this solvation model matches results obtained with more complicated models usually used in refinement procedures in x-ray and neutron experiments but with far fewer parameters. The dramatically improved correspondence between observed and calculated x-ray intensities at low resolution relative to other methods both confirms the validity of the approach used in the MD (molecular dynamics) simulations and allows the results of this study to be implemented in solvent studies on real systems.

A class of triplex-forming oligodeoxyribonucleotides (TFOs) is described that can bind to naturally occurring sites in duplex DNA at physiological pH in the presence of magnesium. The data are consistent with a structure in which the TFO binds in the major groove of double-stranded DNA to form a three-stranded complex that is superficially similar to previously described triplexes. The distinguishing features of this class of triplex are that TFO binding apparently involves the formation of hydrogen-bonded G.GC and T.AT triplets and the TFO is bound antiparallel with respect to the more purine-rich strand of the underlying duplex. Triplex formation is described for targets in the promoter regions of three different genes: the human c-myc and epidermal growth factor receptor genes and the mouse insulin receptor gene. All three sites are relatively GC rich and have a high percentage of purine residues on one strand. DNase I footprinting shows that individual TFOs bind selectively to their target sites at pH 7.4-7.8 in the presence of millimolar concentrations of magnesium. Electrophoretic analysis of triplex formation indicates that specific TFOs bind to their target sites with apparent dissociation constants in the 10(-7)-10(-9) M range. Strand orientation of the bound TFOs was confirmed by attaching eosin or an iron-chelating group to one end of the TFO and monitoring the pattern of damage to the bound duplex DNA. Possible hydrogen-bonding patterns and triplex structures are discussed.

A generalization of the RISM integral equation for site–site pair correlation functions previously proposed by us is discussed and applied to model liquids composed of strongly polar diatomic molecules. The nonuniform molecular charge distribution is represented by the introduction of charged interaction sites. The generalization consists of applying closure conditions analogous to those which are known to be reasonable for the description of atomic ionic fluids, and the corresponding renormalization of the contributions arising from long range forces. We discuss both the symmetry properties of the pair correlation functions in special cases and the dielectric properties implied by theory. Applications are presented for three two-site models which differ substantially in the degree of asymmetry of the non-Coulombic potential between the two sites, and for three three-site models for Br2. The two sites models are compared to computer simulation results, and those for Br2 to experimental results. The analysis shows that the integral equation is well balanced in that in every case the qualitative features of the liquids structure which are introduced by polarity are well represented, even in cases where the site–site potentials are individually much larger than kBT. In cases where the molecular shape and polar forces are in competition, the results are of comparable accuracy to the corresponding theory for nonpolar systems. In the extreme case where changes in orientational structure can occur without interfering with packing requirements, the results appear quantitatively less reliable.