We combined atomistic molecular-dynamics simulations with quantum-mechanical calculations to investigate the sequence dependence of the stretching behavior of duplex DNA. Our combined quantum-mechanical/molecular-mechanical approach demonstrates that molecular-mechanical force fields are able to describe both the backbone and base-base interactions within the highly distorted nucleic acid structures produced by stretching the DNA from the 5' ends, which include conformations containing disassociated basepairs, just as well as these force fields describe relaxed DNA conformations. The molecular-dynamics simulations indicate that the force-induced melting pathway is sequence-dependent and is influenced by the availability of noncanonical hydrogen-bond interactions that can assist the disassociation of the DNA basepairs. The biological implications of these results are discussed. Copyright 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.
Current possibilities and limitations of the simulation of in vivo magnetic resonance spectroscopic signals are demonstrated from the point of view of a simulation software user as well as its programmer. A brief review of the quantum-mechanical background addresses the specific needs of simulation implementation and in vivo MR spectroscopy in general. Practical application examples demonstrate how flexible simulation software, such as NMRScopeB, can be utilized not only for the preparation of metabolite basis signals for quantification of metabolite concentrations, but also in pulse sequence development, assessment of artifacts and analyzing mechanism leading to unexpected signal phenomena.
Guanine radical cation (G•+) is a key intermediate in many oxidative processes occurring in nucleic acids. Here, by combining mixed Quantum Mechanical/Molecular Mechanics calculations and Molecular Dynamics (MD) simulations, we study how the structural behaviour of a tract GGG(TTAGGG)3 (hereafter Tel21) of the human telomeric sequence, folded in an antiparallel quadruple helix, changes when one of the G bases is ionized to G•+ (Tel21+). Once assessed that the electron-hole is localized on a single G, we perform MD simulations of twelve Tel21+ systems, differing in the position of G•+ in the sequence. When G•+ is located in the tetrad adjacent to the diagonal loop, we observe substantial structural rearrangements, which can decrease the electrostatic repulsion with the inner Na+ ions and increase the solvent exposed surface of G•+. Analysis of solvation patterns of G•+ provides new insights on the main reactions of G•+, i.e. the deprotonation at two different sites and hydration at the C8 atom, the first steps of the processes producing 8oxo-Guanine. We suggest the main structural determinants of the relative reactivity of each position and our conclusions, consistent with the available experimental trends, can help rationalizing the reactivity of other G-quadruplex topologies.
- MeSH
- DNA chemistry MeSH
- G-Quadruplexes * MeSH
- Guanine chemistry MeSH
- Ions chemistry MeSH
- Nucleic Acid Conformation MeSH
- Quantum Theory * MeSH
- Humans MeSH
- Models, Molecular MeSH
- Oxidative Stress * MeSH
- Solubility MeSH
- Molecular Dynamics Simulation * MeSH
- Telomere chemistry MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
The semiempirical quantum mechanical (SQM) methods used in drug design are commonly parametrized and tested on data sets of systems that may not be representative models for drug-biomolecule interactions in terms of both size and chemical composition. This is addressed here with a new benchmark data set, PLF547, derived from protein-ligand complexes, consisting of complexes of ligands with protein fragments (such as amino-acid side chains), with interaction energies based on MP2-F12 and DLPNO-CCSD(T) calculations. From these, composite benchmark interaction energies are also built for complexes of the ligand with the complete active site of the protein (PLA15 data set). These data sets are used to test multiple SQM methods with corrections for noncovalent interactions; the role of the solvation model in the calculations is tested as well.
The acid dissociation (ionization) constant pK(a) is one of the fundamental properties of organic molecules. We have evaluated different computational strategies and models to predict the pK(a) values of substituted phenols using partial atomic charges. Partial atomic charges for 124 phenol molecules were calculated using 83 approaches containing seven theory levels (MP2, HF, B3LYP, BLYP, BP86, AM1, and PM3), three basis sets (6-31G*, 6-311G, STO-3G), and five population analyses (MPA, NPA, Hirshfeld, MK, and Löwdin). The correlations between pK(a) and various atomic charge descriptors were examined, and the best descriptors were selected for preparing the quantitative structure-property relationship (QSPR) models. One QSPR model was created for each of the 83 approaches to charge calculation, and then the accuracy of all these models was analyzed and compared. The pK(a)s predicted by most of the models correlate strongly with experimental pK(a) values. For example, more than 25% of the models have correlation coefficients (R²) greater than 0.95 and root-mean-square errors smaller than 0.49. All seven examined theory levels are applicable for pK(a) prediction from charges. The best results were obtained for the MP2 and HF level of theory. The most suitable basis set was found to be 6-31G*. The 6-311G basis set provided slightly weaker correlations, and unexpectedly also, the STO-3G basis set is applicable for the QSPR modeling of pK(a). The Mulliken, natural, and Löwdin population analyses provide accurate models for all tested theory levels and basis sets. The results provided by the Hirshfeld population analysis were also acceptable, but the QSPR models based on MK charges show only weak correlations.
- MeSH
- Models, Chemical MeSH
- Chemistry, Pharmaceutical methods statistics & numerical data MeSH
- Phenols analysis chemistry MeSH
- Kinetics MeSH
- Quantitative Structure-Activity Relationship MeSH
- Quantum Theory MeSH
- Pharmaceutical Preparations analysis chemistry MeSH
- Molecular Conformation MeSH
- Computer Simulation MeSH
- Static Electricity MeSH
- Models, Statistical MeSH
- Publication type
- Journal Article MeSH
A semiempirical quantum mechanical PM6-DH2 method accurately covering the dispersion interaction and H-bonding was used to score fifteen structurally diverse CDK2 inhibitors. The geometries of all the complexes were taken from the X-ray structures and were reoptimised by the PM6-DH2 method in continuum water. The total scoring function was constructed as an estimate of the binding free energy, i.e., as a sum of the interaction enthalpy, interaction entropy and the corrections for the inhibitor desolvation and deformation energies. The applied scoring function contains a clear thermodynamical terms and does not involve any adjustable empirical parameter. The best correlations with the experimental inhibition constants (ln K (i)) were found for bare interaction enthalpy (r (2) = 0.87) and interaction enthalpy corrected for ligand desolvation and deformation energies (r (2) = 0.77); when the entropic term was considered, however, the correlation becomes worse but still acceptable (r (2) = 0.52). The resulting correlation based on the PM6-DH2 scoring function is better than previously published function based on various docking/scoring, SAR studies or advanced QM/MM approach, however, the robustness is limited by number of available experimental data used in the correlation. Since a very similar correlation between the experimental and theoretical results was found also for a different system of the HIV-1 protease, the suggested scoring function based on the PM6-DH2 method seems to be applicable in drug design, even if diverse protein-ligand complexes have to be ranked.
- MeSH
- Cyclin-Dependent Kinase 2 antagonists & inhibitors metabolism MeSH
- Protein Kinase Inhibitors chemistry pharmacology MeSH
- Quantum Theory MeSH
- Humans MeSH
- Ligands MeSH
- Models, Molecular MeSH
- Drug Design MeSH
- Thermodynamics MeSH
- Protein Binding MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Accurate estimation of protein-ligand binding affinity is the cornerstone of computer-aided drug design. We present a universal physics-based scoring function, named SQM2.20, addressing key terms of binding free energy using semiempirical quantum-mechanical computational methods. SQM2.20 incorporates the latest methodological advances while remaining computationally efficient even for systems with thousands of atoms. To validate it rigorously, we have compiled and made available the PL-REX benchmark dataset consisting of high-resolution crystal structures and reliable experimental affinities for ten diverse protein targets. Comparative assessments demonstrate that SQM2.20 outperforms other scoring methods and reaches a level of accuracy similar to much more expensive DFT calculations. In the PL-REX dataset, it achieves excellent correlation with experimental data (average R2 = 0.69) and exhibits consistent performance across all targets. In contrast to DFT, SQM2.20 provides affinity predictions in minutes, making it suitable for practical applications in hit identification or lead optimization.
- MeSH
- Ligands MeSH
- Proteins * metabolism MeSH
- Drug Design * MeSH
- Thermodynamics MeSH
- Protein Binding MeSH
- Publication type
- Journal Article MeSH
The optical activity in porphyrins can easily be induced by a chiral environment, but it is difficult to determine the underlying mechanisms purely on an experimental basis. Therefore, in this study, magnitudes of the perturbational, dipolar, and direct covalent contributions to the electronic circular dichroism (CD) are evaluated with the aid of quantum chemical computations. Electronic properties of model porphyrin chromophores are analyzed. Time-dependent density functional theory (TD DFT), particularly with the hybrid B3LYP functional, appeared suitable for estimation of the electronic excitation energies and spectral intensities. The transition dipole coupling (TDC) between chirally stacked porphyrins was determined as the most important mechanism contributing to their optical activity. This is in agreement with previous experimental observations, where chiral matrices often induce the stacking and large CD signals. About a 10 times smaller signal could be achieved by a chiral orientation of the phenyl or similar residues covalently attached to the porphyrin core. Also, this prediction is in agreement with known experiments. Perturbation models realized by a chirally arranged porphyrin and a point charge, or by a porphyrin and the methane molecule, provided the smallest CD signals. The electrically neutral methane induced similar CD magnitudes as those of the charge, but spectral shapes were different. For a complex of porphyrin and the alanine cation, a significant influence of the solvent on the resultant CD spectral shape was observed, while for the charge and methane perturbations, a negligible solvent effect was found. Detailed dependence of the induced optical activity on variations of geometrical parameters is discussed. The simulations of the induced porphyrin activity can thus bring important information about the structure and intermolecular interactions in chiral complexes.
ACE in a free solution and quantum mechanical density functional theory have been applied to the investigation of interactions of glycine-6-antamanide ([Gly(6) ]AA), a synthetic derivative of cyclic decapeptide antamanide isolated from the highly poisonous mushroom Amanita phalloides, with sodium or potassium ions in methanol. First, from the dependence of effective electrophoretic mobility of [Gly(6) ]AA on Na(+) or K(+) ions concentration in the BGE (methanolic solution of 20 mM chloroacetic acid, 10 mM Tris, pHMeOH 7.8, containing 0-50 mM NaCl or 0-40 mM KCl), the apparent binding (stability) constants of [Gly(6) ]AA-Na(+) and [Gly(6) ]AA-K(+) complexes were evaluated as 26 ± 1 and 14 ± 1 L/mol, respectively. The employed ACE method included correction of the effective mobilities measured at ambient temperature and at variable ionic strength of the BGEs to the mobilities related to the reference temperature 25°C and to the constant ionic strength 10 mM. Second, the interaction energies of the [Gly(6) ]AA-Na(+) and [Gly(6) ]AA-K(+) complexes (-466.3 and -345.2 kJ/mol, respectively) and the structural details of these complexes, such as position of the Na(+) and K(+) ions in the cavity of the [Gly(6) ]AA molecule and the interatomic distances within these complexes, were determined by the density functional theory calculations.
