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Molecular dynamics simulation study is used to investigate the differential effects of three closely-related sterols, cholesterol, ergosterol and lanosterol on the dipalmitoyl phosphatidylcholine membrane. The findings prove that ergosterol is the most efficient of all three, as it helps in promoting the liquid-ordered phase, as well as the lipid domain formation in the membrane.

The chi(C(sub alpha)-C(sub beta) torsional barrier in the dipeptide alanine (N-methyl-L-alanyl-N-methylamide) crystal was investigated using ab initio calculations at various levels of theory, molecular mechanics, and molecular dynamics. It is suggested that environment-catalyzed rotation of methyl groups can occur both in the solid phase and in native biological structures, though the effect might be temperature-dependent.

The cyclic peptide antibiotic Gramicidin S is characterized by the sequence cyclo-(Leu-D-Phe-Pro-Val-Orn)sub 2. To shed light on its molecular dynamics, a simulation of Gramicidin S in dimethyl sulfoxide solution is done. Throughout the simulation, the backbone ring is shown to maintain an antiparallel beta-pleated sheet conformation with two-type II beta-turns. The backbone dihedrals are also shown to be relatively inflexible as they do not undergo any conformational transitions.

A method is developed by using an extended quasi-Gaussian entropy theory parameterized via use of molecular dynamics simulation that provides a complete description of the thermodynamics of peptide conformational states. The method is applied to analyze the conformational thermodynamics of MR121-GSGSW, a peptide that possesses the lowest partial molar entropy.

The atomistic molecular dynamics (MD) simulation is employed to study the significance of methyl groups in the onset of the low-temperature anharmonic dynamics in a crystalline protein. The cavities present in the proteins are found to act as the activation centers of the discussed dynamics.

The internal protein dynamics is described using a model combining Langevin vibration with diffusion. The results have shown that a global description of nanosecond temperature-dependent diffusion and vibrational internal protein dynamics can be obtained by applying the results of the present diffusion-vibration model to the vibrational motions obtained from a normal-mode analysis.

Quantum mechanical/molecular mechanical (QM/MM) reaction-path calculations were used for examining the protein photocycle. The barrier for the thermal cis-trans back-isomerization is lowered by retinal twisting and the rate-limiting barrier for back-isomerization is 5-6 kcal/mol larger than the barrier for the first proton-transfer step.

The modification of internal vibrational modes in a protein due to intraprotein anharmonicity and solvation effects is determined by performing molecular dynamics (MD) simulations of myoglobin. The diagonal and off-diagonal Langevin friction matrix elements, which model the roughness of the vibrational potential energy surfaces, are determined together with the vibrational potentials of mean force from the MD trajectories at 120 K and 300 K in vacuum and in solution.

The Poisson-Boltzman/surface area PB/SA combined with a quantum mechanical description of the ligand in protein/ligand binding affinity calculation is investigated. The result reveals quantum mechanics/molecular mechanics QM/MM is promising new avenue for automated docking and scoring of flexible ligands.

The vibrational entropy change on the burial of a crystallographically well-ordered water molecule in bovine pancreatic trypsin inhibitor (BPTI) using normal-mode analysis is dissected. A detailed analysis is performed of how the translational and rotational degrees of freedom of the isolated water molecule are transformed into vibrational modes in the complex.

An analytical approach is developed for reconstructingsite-specificmethyl-bearing protein side-chain conformational energy surfaces fromNMR methyl axis order parameters (Oaxis2). Application of an enhancedsampling algorithm (adaptive biasing force) to molecular dynamicssimulation of a protein, calcium-bound calmodulin, reveals a nonlinearcorrelation between Oaxis2and the populations of rotamer statesof protein side-chains, permitting the rotamer populations to be extracteddirectly from Oaxis2. The analytical approach yields side-chainconformational distributions that are in excellent agreement withthose obtained from the enhanced-sampling MD results. [ABSTRACT FROM AUTHOR]

The heterogeneous fast side-chain dynamics of proteins plays crucial roles in molecular recognition and binding. Site-specific NMR experiments quantify these motions by measuring the model-free order parameter ( O axis 2 ) on a scale of 0 (most flexible) to 1 (least flexible) for each methyl-containing residue of proteins. Here, we have examined ligand-induced variations in the fast side-chain dynamics and conformational entropy of calmodulin (CaM) using five different CaM-peptide complexes. O axis 2 of CaM in the ligand-free ( O axis,U 2 ) and ligand-bound ( O axis,B 2 ) states are calculated from molecular dynamics trajectories and conformational energy surfaces obtained using the adaptive biasing force (ABF) method. Δ O axis 2 = O axis,B 2 - O axis,U 2 follows a Gaussian-like unimodal distribution whose second moment is a potential indicator of the binding affinity of these complexes. The probability for the binding-induced O axis,U 2 → O axis,B 2 transition decreases with increasing magnitude of Δ O axis 2 , indicating that large flexibility changes are improbable for side chains of CaM after ligand binding. A linear correlation established between Δ O axis 2 and the conformational entropy change of the protein makes possible the determination of the conformational entropy of binding of protein-ligand complexes. The results not only underscore the functional importance of fast side-chain fluctuations but also highlight key motional and thermodynamic correlates of protein-ligand binding.

Sodium ions have long been known to reduce the binding of agonists in many class-A GPCRs while having little effect on antagonist binding. Here, using long-time scale classical all-atom molecular dynamics simulations, we explore, in atomic detail, the motion of sodium ions within the ligand-binding pocket of the A 2A adenosine receptor (A2A-AR) both in the presence and absence of ligands and in the active and inactive state. We identify novel secondary ion binding sites within the pocket and find that the types of ion motions within the pocket are highly dependent on the presence and type of ligand within the pocket. Our results provide a first step toward developing a molecular understanding of the impact of sodium ions on class-A GPCRs.

The interface between biological matter and inorganic materials is a widely investigated research topic due to possible applications in biomedicine and nanotechnology. In this context, the molecular level adsorption mechanism that drives specific recognition between small peptide sequences and inorganic surfaces represents an important topic likely to provide much information useful for designing bioderived materials. Here, we investigate the dynamics at the interface between a Ti-binding peptide sequence (AMRKLPDAPGMHC) and a TiO 2 anatase surface by using molecular dynamics (MD) simulations. In the simulations the adsorption mechanism is characterized by diffusion of the peptide from the bulk water phase toward the TiO 2 surface, followed by the anchoring of the peptide to the surface. The anchoring is mediated by the interfacial water layers by means of the charged groups of the side chains of the peptide. The peptide samples anchored and dissociated states from the surface and its conformation is not affected by the surface when anchored.

Relaxation of the twisted-retinal photoproduct state triggers proton-coupled reaction cycle in retinal proteins. Given the crowded protein environments in which the retinal resides, a key open question is whether the retinal relaxation path is governed by the intrinsic torsional properties of the retinal or rather by the interactions of the retinal with protein and water groups. Here we address this question by performing systematic quantum mechanical/molecular mechanical molecular dynamics computations of retinal dynamics in bacteriorhodopsin at different temperatures, reaction path computations, and assessment of the vibrational fingerprints of the retinal molecule. The results demonstrate a complex dependence of the retinal dynamics and preferred geometry on temperature. As the temperature increases, the retinal dihedral angle samples values largely determined by its internal conformational energy. The protein environment shapes the energetics of retinal relaxation and provides hydrogen-bonding partners that stabilize the retinal geometry.

Large-scale ensemble docking is investigated using five proteins from the Directory of Useful Decoys (DUD, dud.docking.org ) for which docking to crystal structures has proven difficult. Molecular dynamics trajectories are produced for each protein and an ensemble of representative conformational structures extracted from the trajectories. Docking calculations are performed on these selected simulation structures and ensemble-based enrichment factors compared with those obtained using docking in crystal structures of the same protein targets or random selection of compounds. Simulation-derived snapshots are found with improved enrichment factors that increase the chemical diversity of docking hits for four of the five selected proteins. A combination of all the docking results obtained from molecular dynamics simulation followed by selection of top-ranking compounds appears to be an effective strategy for increasing the number and diversity of hits when using docking to screen large libraries of chemicals against difficult protein targets.

Ionic liquids have become a popular solvent for cellulose pretreatment in biorefineries due to their efficiency in dissolution and their reusability. Understanding the interactions between cations, anions, and cellulose is key to the development of better solvents and the improvement of pretreatment conditions. While previous studies described the interactions between ionic liquids and cellulose fibers, shedding light on the initial stages of the cellulose dissolution process, we study the end state of that process by exploring the structure and dynamics of a single cellulose decamer solvated in 1-butyl-3-methyl-imidazolium chloride (BmimCl) and in water using replica-exchange molecular dynamics. In both solvents, global structural features of the cellulose chain are similar. However, analyses of local structural properties show that cellulose explores greater conformational variability in the ionic liquid than in water. For instance, in BmimCl the cellulose intramolecular hydrogen bond O3H'···O5 is disrupted more often resulting in greater flexibility of the solute. Our results indicate that the cellulose chain is more dynamic in BmimCl than in water, which may play a role in the favorable dissolution of cellulose in the ionic liquid. Calculation of the configurational entropy of the cellulose decamer confirms its higher conformational flexibility in BmimCl than in water at elevated temperatures.

Protein solvation dynamics has been investigated using atom-dependent Langevin friction coefficients derived directly from molecular dynamics (MD) simulations. To determine the effect of solvation on the atomic friction coefficients, solution and vacuum MD simulations were performed for lysozyme and staphylococcal nuclease and analyzed by Langevin mode analysis. The coefficients thus derived are roughly correlated with the atomic solvent-accessible surface area (ASA), as expected from the fact that friction occurs as the result of collisions with solvent molecules. However, a considerable number of atoms with higher friction coefficients are found inside the core region. Hence, the influence of solvent friction propagates into the protein core. The internal coefficients have large contributions from the low-frequency modes, yielding a simple picture of the surface-to-core long-range damping via solvation governed by collective low-frequency modes. To make use of these findings in implicit-solvent modeling, we compare the all-atom friction results with those obtained using Langevin dynamics (LD) with two empirical representations: the constant-friction and the ASA-dependent (Pastor-Karplus) friction models. The constant-friction model overestimates the core and underestimates the surface damping whereas the ASA-dependent friction model, which damps protein atoms only on the solvent-accessible surface, reproduces well the friction coefficients for both the surface and core regions observed in the explicit-solvent MD simulations. Therefore, in LD simulation, the solvent friction coefficients should be imposed only on the protein surface.

Organophosphorus (OP) nerve agents such as (S)-sarin are among the most highly toxic compounds that have been synthesized. Engineering enzymes that catalyze the hydrolysis of nerve agents ("bioscavengers") is an emerging prophylactic approach to diminish their toxic effects. Although its native function is not known, diisopropyl fluorophosphatase (DFPase) from Loligo vulgaris catalyzes the hydrolysis of OP compounds. Here, we investigate the mechanisms of diisopropylfluorophosphate (DFP) and (S)-sarin hydrolysis by DFPase with quantum mechanical/molecular mechanical umbrella sampling simulations. We find that the mechanism for hydrolysis of DFP involves nucleophilic attack by Asp229 on phosphorus to form a pentavalent intermediate. P-F bond dissociation then yields a phosphoacyl enzyme intermediate in the rate-limiting step. The simulations suggest that a water molecule, coordinated to the catalytic Ca(2+), donates a proton to Asp121 and then attacks the tetrahedral phosphoacyl intermediate to liberate the diisopropylphosphate product. In contrast, the calculated free energy barrier for hydrolysis of (S)-sarin by the same mechanism is highly unfavorable, primarily because of the instability of the pentavalent phosphoenzyme species. Instead, simulations suggest that hydrolysis of (S)-sarin proceeds by a mechanism in which Asp229 could activate an intervening water molecule for nucleophilic attack on the substrate. These findings may lead to improved strategies for engineering DFPase and related six-bladed β-propeller folds for more efficient degradation of OP compounds.

Understanding biomass structure and dynamics on multiple time and length scales is important for the development of cellulosic biofuels. To this aim, we have developed a coarse-grain (CG) model for molecular dynamics (MD) simulations of cellulose fibrils in explicit water based on target observables from fully atomistic simulations. This model examines the significance of the presence of explicit solvent and compares results with the previous, implicit solvent CG cellulose models. The present, constraint-free CG model is used to generate a series of noncrystalline fibril structures using a coupling parameter, λ, between fully crystalline and fully amorphous potentials. By exploring various structural parameters, including the root-mean-square deviation, root-mean-square fluctuations, radius of gyration, and persistence length, we find the crystalline-to-amorphous state transition takes place at λ ≈ 0.386. The persistence length of cellulose fibril in the transition region corresponds to that of native cellulose fibrils. The transition between crystalline and amorphous fibrils occurs at larger values of λ in explicit water than in the implicit case. Detailed analysis of individual energetic contribution to the transition reveals that the nonbonded interactions, in particular, that of cellulose-water interaction, plays a significant role in the observed crystalline to amorphous transition of cellulose fibril. The present study thus highlights the importance of solvent presence that cannot be adequately described with the previous implicit solvent model. The present method provides an accurate and constraint-free approach for deriving a variety of structures of cellulose in water, with a wide range of crystallinity, suitable for incorporation into large-scale models of lignocellulosic biomass.

Lignin is a complex, branched polymer that reinforces plant tissue. Understanding the factors that govern lignin structure is of central importance to the development of technologies for converting lignocellulosic biomass into fuels because lignin imparts resistance to chemical, enzymatic, and mechanical deconstruction. Lignin is formed by enzymatic oxidation of phenolic monomers (monolignols) of three main types, guaiacyl (G), syringyl (S), and p-hydroxyphenyl (H) subunits. It is known that increasing the relative abundance of H subunits results in lower molecular weight lignin polymers and hence more easily deconstructed biomass, but it is not known why. Here, we report an analysis of frontier molecular orbitals in mono-, di-, and trilignols, calculated using density functional theory, which points to a requirement of strong p-electron density on the reacting phenolic oxygen atom of the neutral precursor for enzymatic oxidation to occur. This model is consistent with a proton-coupled electron transfer (PCET) mechanism and for the first time explains why H subunits in certain linkages (β-β or β-5) react poorly and tend to "cap" the polymer. In general, β-5 linkages with either a G or H terminus are predicted to inhibit elongation. More broadly, the model correctly accounts for the reactivity of the phenolic groups in a diverse set of dilignols comprising H and G subunits. Thus, we provide a coherent framework for understanding the propensity toward growth or termination of different terminal subunits in lignin.

The relationship between the NMR methyl group axial order parameter and the side chain conformational entropy is investigated in inhibitor-bound and apo human HIV protease using molecular dynamics simulation. Three distinct entropic classes of methyl-bearing side chains, determined by the topological distance of the methyl group from the protein backbone (i.e., the number of χ-bonds between the Cα and the carbon of the CH3 group), are revealed by atomistic trajectory analyses performed in the local frame of reference of individual methyl probes. The results demonstrate that topologically equivalent methyl groups experience similar nonbonded microenvironments regardless of the type of residues to which they are attached. Similarly, methyl groups that belong to the same side chain but that are not topologically equivalent exhibit different thermodynamic and dynamic properties. The two-parameter classification (based upon entropy and methyl axial order parameter) of side chains described here permits improved estimates of the conformational entropies of proteins from NMR motional parameters.

The derivation of mean-square displacements from elastic incoherent neutron scattering (EINS) of proteins is examined, with the aid of experiments on camphor-bound cytochrome P450cam and complementary molecular dynamics simulations. It is shown that a q(4) correction to the elastic incoherent structure factor (where q is the scattering vector) can be simply used to reliably estimate from the experiment both the average mean-square atomic displacement, <Δr(2)> of the nonexchanged hydrogen atoms in the protein and its variance, σ(2). The molecular dynamics simulation results are in broad agreement with the experimentally derived <Δr(2)> and σ(2) derived from EINS on instruments at two different energy resolutions, corresponding to dynamics on the ∼100 ps and ∼1 ns time scales. Significant dynamical heterogeneity is found to arise from methyl-group rotations. The easy-to-apply q(4) correction extends the information extracted from elastic incoherent neutron scattering experiments and should be of wide applicability.

Lignin is a complex, heterogeneous polymer in plant cell walls that provides mechanical strength to the plant stem and confers resistance to degrading microbes, enzymes, and chemicals. Lignin synthesis initiates through oxidative radical-radical coupling of monolignols, the most common of which are p-coumaryl, coniferyl, and sinapyl alcohols. Here, we use density functional theory to characterize radical-radical coupling reactions involved in monolignol dimerization. We compute reaction enthalpies for the initial self- and cross-coupling reactions of these monolignol radicals to form dimeric intermediates via six major linkages observed in natural lignin. The 8-O-4, 8-8, and 8-5 coupling are computed to be the most favorable, whereas the 5-O-4, 5-5, and 8-1 linkages are less favorable. Overall, p-coumaryl self- and cross-coupling reactions are calculated to be the most favorable. For cross-coupling reactions, in which each radical can couple via either of the two sites involved in dimer formation, the more reactive of the two radicals is found to undergo coupling at its site with the highest spin density.

Neutron scattering experiments have demonstrated that binding of the cancer drug methotrexate softens the low-frequency vibrations of its target protein, dihydrofolate reductase (DHFR). Here, this softening is fully reproduced using atomic detail normal-mode analysis. Decomposition of the vibrational density of states demonstrates that the largest contributions arise from structural elements of DHFR critical to stability and function. Mode-projection analysis reveals an increase of the breathing-like character of the affected vibrational modes consistent with the experimentally observed increased adiabatic compressibility of the protein on complexation.

The change of protein vibrations on ligand binding is of functional and thermodynamic importance. Here, this process is characterized using a simple analytical "ball-and-spring" model and all-atom normal-mode analysis (NMA) of the binding of the cancer drug, methotrexate (MTX) to its target, dihydrofolate reductase (DHFR). The analytical model predicts that the coupling between protein vibrations and ligand external motion generates entropy-rich, low-frequency vibrations in the complex. This is consistent with the atomistic NMA which reveals vibrational softening in forming the DHFR-MTX complex, a result also in qualitative agreement with neutron-scattering experiments. Energy minimization of the atomistic bound-state (B) structure while gradually decreasing the ligand interaction to zero allows the generation of a hypothetical "intermediate" (I) state, without the ligand force field but with a structure similar to that of B. In going from I to B, it is found that the vibrational entropies of both the protein and MTX decrease while the complex structure becomes enthalpically stabilized. However, the relatively weak DHFR:MTX interaction energy results in the net entropy gain arising from coupling between the protein and MTX external motion being larger than the loss of vibrational entropy on complex formation. This, together with the I structure being more flexible than the unbound structure, results in the observed vibrational softening on ligand binding.