Search

A polarizable environment, prominently the solvent, responds to electronic changes in biomolecules rapidly. The knowledge of conformational relaxation of the biomolecule itself, however, may be scarce or missing. In this work, we describe in detail the structural changes in DNA undergoing electron transfer between two adjacent nucleobases. We employ an approach based on averaging of tens to hundreds of thousands of nonequilibrium trajectories generated with molecular dynamics simulation, and a reduction of dimensionality suitable for DNA. We show that the conformational response of the DNA proceeds along a single collective coordinate that represents the relative orientation of two consecutive base pairs, namely, a combination of helical parameters shift and tilt. The structure of DNA relaxes on time scales reaching nanoseconds, contributing marginally to the relaxation of energies, which is dominated by the modes of motion of the aqueous solvent. The concept of reaction path averaging (RPA), conveniently exploited in this context, makes it possible to filter out any undesirable noise from the nonequilibrium data, and is applicable to any chemical process in general. [ABSTRACT FROM AUTHOR]

The accuracy and performance of implicitsolvent methods for solvationfree energy calculations were assessed on a set of 20 neutral drugmolecules. Molecular dynamics (MD) provided ensembles of conformationsin water and water-saturated octanol. The solvation free energieswere calculated by popular implicit solvent models based on quantummechanical (QM) electronic densities (COSMO-RS, MST, SMD) as wellas on molecular mechanical (MM) point-charge models (GB, PB). Theperformance of the implicit models was tested by a comparison withexperimental water–octanol transfer free energies (ΔGow) by using single- and multiconformation approaches.MD simulations revealed difficulties in a priori estimation of theflexibility features of the solutes from simple structural descriptors,such as the number of rotatable bonds. An increasing accuracy of thecalculated ΔGowwas observed inthe following order: GB1 ∼ PB < GB7 ≪ MST < SMD∼ COSMO-RS with a clear distinction identified between MM-and QM-based models, although for the set excluding three largestmolecules, the differences among COSMO-RS, MST, and SMD were negligible.It was shown that the single-conformation approach applied to crystalgeometries provides a rather accurate estimate of ΔGowfor rigid molecules yet fails completely for the flexibleones. The multiconformation approaches improved the performance, butonly when the deformation contribution was ignored. It was revealedthat for large-scale calculations on small molecules a recent GB model,GB7, provided a reasonable accuracy/speed ratio. In conclusion, thestudy contributes to the understanding of solvation free energy calculationsfor physical and medicinal chemistry applications. [ABSTRACT FROM AUTHOR]

A DNA dodecamer and the methyladenine···methylthymine (mA···mT) complex in aqueous environment have been studied by means of molecular dynamics simulation, with a modified force field accounting for the hypothetical absence of London dispersion forces. Under these conditions, the mA···mT complex is preserved, while the double-helical DNA oligomer passes via an extended, ladder-like intermediate to a collapsed structure. The results are interpreted in terms of stability and specificity of the structure of studied complexes. While the hydrophobic effect of the solvent accounts for the sufficient stabilization of the complex, the appearance of the native biomolecular conformation is attributed to the London dispersion forces. Thus, the London dispersion seems to provide the native structure of a biomolecular complex with the largest additional stabilization, preferring it among several (or many) possible aggregated structures. The observations are affected by the construction of the modified force field, and this effect is discussed thoroughly. The fundamental issues are the coupling of the components of the Lennard-Jones potential and the way to separate them. Based on the observations, the description of nonbonded interactions with the current biomolecular force fields is discussed. It is proposed that a novel force field composed of physically correct components to describe nonbonded interactions could exhibit more favorable performance in certain up-to-date applications.

We investigated the intercalation of an antitumor drug ellipticine into four adenine-thymine (AT) rich DNA duplexes with the focus on the configurational entropy, by means of molecular dynamics (MD) simulations. Two possible binding orientations of ellipticine in a DNA double helix were studied, and the orientation with the pyrrole nitrogen exposed into a major groove was identified as the more probable. The configurational entropy change of DNA is shown to contribute significantly to the binding free energy. The magnitude of this contribution depends on the exact DNA sequence. A detailed analysis revealed that the largest flexibility changes occurred in the sugar-phosphate backbone, resulting in an entropy gain in the most cases. The nucleobases were not involved in the changes of flexibility and entropy. BI/BII-like conformational transitions were observed after the intercalation of ellipticine, and the consequences of these transitions for the evaluation of entropy are discussed.