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We investigate theelectrostatics, energetics, and dynamics ofdendrimer–DNA interactions that mimic protein–DNA complexesas a means to design facilitated mechanisms by which dendrimers canslide and search DNA for targets. By using all-atom molecular dynamicssimulations, we calculated the free energy profiles of dendrimer-bindingaround the DNA via umbrella sampling. We also calculated electrostaticinteraction maps in comparison to proteins, as well as the dynamicalchanges induced by DNA–dendrimer interactions via NMR-measurableorder parameters. Our results show that for dendrimers to go aroundDNA, there is a free-energy barrier of 8.5 kcal/mol from the DNA majorgroove to DNA minor groove, with a minimum in the major groove. Thisbarrier height makes it unlikely for an all-amine dendrimer to slidealong DNA longitudinally, but following a helical path may be possiblealong the major groove. Comparison of the nonbonded interaction energyand the interaction free-energy profiles reveal a considerable entropiccost as the dendrimer binds to DNA. This is also supported by themobility patterns obtained from NMR-measurable order parameter values,which show a decreased mobility of the dendrimer N–H bond vectorsin the DNA-binding mode. [ABSTRACT FROM AUTHOR]

We combined molecular dynamics based free energy calculations with sum frequency generation (SFG) spectroscopy to study the orientational distribution of solvated peptides near hydrophobic surfaces. Using a simplified atomistic model of the polystyrene (PS) surface, molecular dynamics simulations have been applied to compute the orientational probability of an α-helical peptide, magainin 2, with respect to the PS/water interface. Free energy calculations revealed that the preferred (horizontal) peptide orientation was driven by the favorable interactions between the hydrophobic PS surface and the hydrophobic residues on the helix, and additional simulations examined the importance of small aggregate formation. Concentration-dependent measurements obtained via SFG vibrational spectroscopy suggest that, at very low peptide concentrations, magainin molecules tend to lie down at the PS/solution interface, which correlates well with the simulation results. When the concentration is increased, peptides exhibit behavior not captured by MD simulations using single helical peptides. A combination of simulations and experiments was shown to yield more reliable results with molecular-level insights into interaction between peptides and polymer surfaces. [ABSTRACT FROM AUTHOR]

Dynamic disorder in proteins, as demonstrated by variations in single-molecule electron transfer rates, is investigated by molecular dynamics simulations. The potential of mean force for the fluctuating donor−acceptor distance is calculated for the NAD(P)H:flavin oxidoreductase (Fre) complex with flavin adenine dinucleotide (FAD) and is found to be in agreement with that estimated from electron transfer experiments. The calculated autocorrelation function of the distance fluctuations has a simple exponential behavior at low temperatures and stretched exponential behavior at higher temperatures on femtosecond to nanosecond time scales. This indicates that the calculated dynamic disorder arises from a wide range of trapping times in potential wells on the protein energy landscape and suggests a corresponding origin for the stretched exponential behavior observed experimentally on longer time scales. [ABSTRACT FROM AUTHOR]

Sequence-specific DNA flexibility plays a key role in a variety of cellular interactions that are critical for gene packaging, expression, and regulation, yet few studies have experimentally explored the sequence dependence of DNA dynamics that occur on biologically relevant time scales. Here, we use nuclear magnetic resonance (NMR) carbon spin relaxation combined with molecular dynamics (MD) simulations to examine the picosecond to nanosecond dynamics in a variety of dinucleotide steps as well as in varying length homopolymeric An·Tn repeats (An-tracts, where n = 2, 4, or 6) that exhibit unusual structural and mechanical properties. We extend the NMR spin relaxation time scale sensitivity deeper into the nanosecond regime by using glycerol and a longer DNA duplex to slow overall tumbling. Our studies reveal a structurally unique A-tract core (for n > 3) that is uniformly rigid, flanked by junction steps that show increasing sugar flexibility with A-tract length. High sugar mobility is observed at pyrimidine residues at the A-tract junctions, which is encoded at the dinucleotide level (CA, TG, and CG steps) and increases with A-tract length. The MD simulations reproduce many of these trends, particularly the overall rigidity of A-tract base and sugar sites, and suggest that the sugar-backbone dynamics could involve transitions in sugar pucker and phosphate backbone BI ↔ BII equilibria. Our results reinforce an emerging view that sequence-specific DNA flexibility can be imprinted in dynamics occurring deep within the nanosecond time regime that is difficult to characterize experimentally at the atomic level. Such large-amplitude sequence-dependent backbone fluctuations might flag the genome for specific DNA recognition. [ABSTRACT FROM AUTHOR]

Recent advances in the collection and interpretation of surface-sensitive vibrational spectroscopic measurements have made it possible to study the orientation of peptides and proteins in situ in a biologically relevant environment. However, interpretation of sum frequency generation (SFG) and attenuated total reflectance Fourier transform infrared (ATR-FTIR) vibrational spectroscopy is hindered by the fact that orientation cannot be inferred without some prior knowledge of the protein structure. In this work, molecular dynamics simulations were used to study the interfacial orientation and structural deformation of the short β-sheet peptide tachyplesin I at the polystyrene/water interface. By combining these results with ATR-FTIR and SFG measurements, reasonable agreement was found with the simulation results, suggesting that tachyplesin I lies parallel to the surface, although the simulation results imply a broader distribution of peptide twist angles than could be characterized using available experimental measurements. The interfacial structure was found to be deformable even when disulfide bonds were preserved, and these local deviations from a purely extended β-sheet conformation may be of importance to future developments in the interpretation of SFG and ATR-FTIR spectra. [ABSTRACT FROM AUTHOR]

Nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics (MD) simulations are both techniques that can be used to characterize the structural dynamics of biomolecules and their underlying time scales. Comparison of relaxation parameters obtained through each methodology allows for cross validation of techniques and for complementarity in the analysis of dynamics. Here we present a combined NMR/MD study of the dynamics of HIV-1 transactivation response (TAR) RNA. We compute relaxation constants (R1, R2, and NOE) and model-free parameters (S2and τ) from a 65 ns molecular dynamics (MD) trajectory and compare them with the respective parameters measured in a domain-elongation NMR experiment. Using the elongated domain as the frame of reference for all computed parameters allows for a direct comparison between experiment and simulation. We see good agreement for many parameters and gain further insight into the nature of the local and global dynamics of TAR, which are found to be quite complex, spanning multiple time scales. For the few cases where agreement is poor, comparison of the dynamical parameters provides insight into the limits of each technique. We suggest a frequency-matching procedure that yields an upper bound for the time scale of dynamics to which the NMR relaxation experiment is sensitive. [ABSTRACT FROM AUTHOR]

The molecular structures and enthalpy release of poly(amidoamine) (PAMAM) dendrimers binding to 1,2-dimyristoyl- sn-glycero-3-phosphocholine (DMPC) bilayers were explored through atomistic molecular dynamics. Three PAMAM dendrimer terminations were examined: protonated primary amine, neutral acetamide, and deprotonated carboxylic acid. Fluid and gel lipid phases were examined to extract the effects of lipid tail mobility on the binding of generation-3 dendrimers, which are directly relevant to the nanoparticle interactions involving lipid rafts, endocytosis, lipid removal, and/or membrane pores. Upon binding to gel phase lipids, dendrimers remained spherical, had a constant radius of gyration, and approximately one-quarter of the terminal groups were in close proximity to the lipids. In contrast, upon binding to fluid phase bilayers, dendrimers flattened out with a large increase in their asphericity and radii of gyration. Although over twice as many dendrimer−lipid contacts were formed on fluid versus gel phase lipids, the dendrimer−lipid interaction energy was only 20% stronger. The greatest enthalpy release upon binding was between the charged dendrimers and the lipid bilayer. However, the stronger binding to fluid versus gel phase lipids was driven by the hydrophobic interactions between the inner dendrimer and lipid tails. [ABSTRACT FROM AUTHOR]

Third-generation (G3) poly(amidoamine) (PAMAM) dendrimers are simulated approaching 1,2-dimyristoyl- sn-glycero-3-phosphocholine (DMPC) bilayers with fully atomistic molecular dynamics, which enables the calculation of a free energy profile along the approach coordinate. Three different dendrimer terminations are examined: protonated primary amine, uncharged acetamide, and deprotonated carboxylic acid. As the dendrimer and lipids become closer, their attractive force increases (up to 240 pN) and the dendrimer becomes deformed as it interacts with the lipids. The total energy release upon binding of a G3−NH 3+, G3−Ac, or G3−COO −dendrimer to a DMPC bilayer is, respectively, 36, 26, or 47 kcal/mol or, equivalently, 5.2, 3.2, or 4.7 × 10 −3kcal/g. These results are analyzed in terms of the dendrimers’ size, shape, and atomic distributions as well as proximity of individual lipid molecules and particular lipid atoms to the dendrimer. For example, an area of 9.6, 8.2, or 7.9 nm 2is covered on the bilayer for the G3−NH 3+, G3−Ac, or G3−COO −dendrimers, respectively, while interacting strongly with 18−13 individual lipid molecules. [ABSTRACT FROM AUTHOR]