Biomedical subjects

Aatto Laaksonen

Publications and source records attributed to Aatto Laaksonen.

12 recordsLinked to original sources

PubMed2006

Preferential solvation of phenol in binary solvent mixtures. A molecular dynamics study.

Molecular dynamics computer simulations were carried out to study the preferential solvation of phenol in equimolar acetonitrile-water and ethanol-water binary mixtures. Two water models were used to investigate the model dependence of preferential solvation. The results are compared to recent intermolecular 1H NOESY experiments reported on the same systems. In the case of acetonitrile-water the local mole fraction obtained from simulations agrees quite well with experiments. In the case of ethanol-water there was a qualitative difference, which was observed for both water models. However, when comparing the degree of preferential solvation of the two cosolvents ethanol and acetonitrile with each of the two water models, the trend obtained from the simulations agrees with experimental data.

Journal Article↗

PubMed2006

DNA strand break: structural and electrostatic properties studied by molecular dynamics simulation.

Due to their lethal consequences and a relatively high probability of introduction of repair errors and mutations, single and double strand breaks are among the most important and dangerous DNA lesions. However, the mechanisms of their recognition and repair processes are only poorly known at present. This work defines and analyzes a DNA with single strand break as a template study for future complex analyses of biologically serious double strand break damage and its enzymatic repair mechanisms. Besides a non-damaged DNA serving as a reference system with no surprising results, system with open valences of the atoms at the strand break ends as well as a system with filled valences were simulated. In both cases during the first few nanoseconds the broken ends of strand breaks are significantly exposed to the outside of the molecule. However, with increasing time, the system with single strand break with open valences is partially disrupted. On the contrary, the system with filled valences shows stable conformation with newly created hydrogen bond between the two strand break endings. Moreover, these endings are steadily situated in the inner part of the molecule, thus making the recognition and docking process of a repair enzyme more complicated in the case of filled valences.

Computational Biology↗

PubMed2005

Theoretical study of the human DNA repair protein HOGG1 activity.

We have examined the role of the catalytic lysine (Lys 249) in breaking the glycosidic bond of 8-oxoguanine in the enzyme human 8-oxoguanine DNA glycosylase. Until quite recently it has been assumed that this lysine acts as a nucleophile in an S(N)2 type of reaction after being activated through a donation of a proton to a strictly conserved aspartate, also located in the active site. However, evidence from crystallographic, as well as biochemical studies, questions this assumption mainly because the lysine is not ideally positioned for such an attack. In addition, the catalytic activity is preserved even after that aspartate is mutated to a residue not accepting protons, but still keeping the interactions in the active site. In this study, we have investigated several different reaction mechanisms to discover plausible ways where the lysine could assist in breaking the glycosidic bond. We use hybrid density functional theory to characterize both associative and dissociative pathways. We find that the smallest energetical barrier involves an S(N)1 type of mechanism where the lysine electrostatically stabilizes the dissociating base and then donates a proton with a very small barrier and then finally attacks the sugar ring to create the covalently bound protein-DNA intermediate complex. The S(N)2 mechanism also has a lower barrier than the "spontaneous" bond breaking but considerably above that of the S(N)1 reaction. However, in current conditions, the reactants placed in a conformation posed for an S(N)2 reaction is substantially more stable than if posed for the S(N)1 reaction, indicating that the active site has to bind stronger to the latter in order to achieve a full catalytic effect. An analysis of the polarization of the transition states shows that the polarization is largest for the S(N)1 reaction, indicating that this path will gain most by being placed in a prepolarized active site. These findings give further support to the hypothesis that a dissociative mechanism may be the preferred mode of action for this type of enzymes.

Binding Sites↗

PubMed2004

Molecular interaction model for the C1B domain of protein kinase C-gamma in the complex with its activator phorbol-12-myristate-13-acetate in water solution and lipid bilayer.

Detailed molecular models of the free C1B domain of protein kinase C-gamma (PKC-gamma) and the C1B domain with its activator phorbol-12-myristate-13-acetate (PMA) in water solution and in the presence of dipalmitoylphosphatidylcholine (DPPC) bilayer are presented. Molecular dynamics of the free C1B domain reveals hydrogen bonds, which are critical for the forming of the diacylglycerols/phorbol esters binding site, and indicates the important role of Gln27 for the geometry of this site. According to the model, PMA interacts with the C1B domain by hydrophobic interactions with Pro11 and Tyr22 and by three persistent hydrogen bonds between the C3 carbonyl group of PMA and Gly23 and between the C20 hydroxyl group of PMA and the Leu21 and Thr12 residues of the C1B domain. The C9 hydroxyl group of PMA does not interact with the C1B domain, but it is involved in the interaction with the DPPC bilayer. Two preferential orientations of the C1B-PMA complex toward the DPPC bilayer resulted from our molecular modeling study.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed2004

A molecular dynamics simulation study of polyamine- and sodium-DNA. Interplay between polyamine binding and DNA structure.

Four different molecular dynamics (MD) simulations have been performed for infinitely long ordered DNA molecules with different counterions, namely the two natural polyamines spermidine(3+) (Spd3+) and putrescine(2+) (Put2+), the synthetic polyamine diaminopropane(2+) (DAP2+), and the simple monovalent cation Na+. All systems comprised a periodical hexagonal cell with three identical DNA decamers, 15 water molecules per nucleotide, and counterions balancing the DNA charge. The simulation setup mimics the DNA state in oriented DNA fibers, previously studied using NMR and other experimental methods. In this paper the interplay between polyamine binding and local DNA structure is analyzed by investigating how and if the minor groove width of DNA depends on the presence and dynamics of the counterions. The results of the MD simulations reveal principal differences in the polyamine-DNA interactions between the natural [spermine(4+), Spd3+, Put2+] and the synthetic (DAP2+) polyamines.

Base Sequence↗

PubMed2004

Molecular dynamics simulation study of oriented polyamine- and Na-DNA: sequence specific interactions and effects on DNA structure.

Molecular dynamics (MD) computer simulations have been carried out on four systems that correspond to an infinite array of parallel ordered B-DNA, mimicking the state in oriented DNA fibers and also being relevant for crystals of B-DNA oligonucleotides. The systems were all comprised of a periodical hexagonal cell with three identical DNA decamers, 15 water molecules per nucleotide, and counterions balancing the DNA charges. The sequence of the double helical DNA decamer was d(5'-ATGCAGTCAG)xd(5'-TGACTGCATC). The counterions were the two natural polyamines spermidine(3+) (Spd(3+)) and putrescine(2+) (Put(2+)), the synthetic polyamine diaminopropane(2+) (DAP(2+)), and the simple monovalent cation Na(+). This work compares the specific structures of the polyamine- and Na-DNA systems and how they are affected by counterion interactions. It also describes sequence-specific hydration and interaction of the cations with DNA. The local DNA structure is dependent on the nature of the counterion. Even the very similar polyamines, Put(2+) and DAP(2+), show clear differences in binding to DNA and in effect on hydration and local structure. Generally, the polyamines disorder the hydration of the DNA around their binding sites whereas Na(+) being bound to DNA attracts and organizes water in its vicinity. Cation binding at the selected sites in the minor and in the major groove is compared for the different polyamines and Na(+). We conclude that the synthetic polyamine (DAP(2+)) binds specifically to several structural and sequence-specific motifs on B-DNA, unlike the natural polyamines, Spd(3+) and Put(2+). This specificity of DAP(2+) compared to the more dynamic behavior of Spd(3+) and Put(2+) may explain why the latter polyamines are naturally occurring in cells.

Base Sequence↗

PubMed2004

Determination of solvation free energies by adaptive expanded ensemble molecular dynamics.

A new method of calculating absolute free energies is presented. It was developed as an extension to the expanded ensemble molecular dynamics scheme and uses probability density estimation to continuously optimize the expanded ensemble parameters. The new method is much faster as it removes the time-consuming and expertise-requiring step of determining balancing factors. Its efficiency and accuracy are demonstrated for the dissolution of three qualitatively very different chemical species in water: methane, ionic salts, and benzylamine. A recently suggested optimization scheme by Wang and Landau [Phys. Rev. Lett. 86, 2050 (2001)] was also implemented and found to be computationally less efficient than the proposed adaptive expanded ensemble method.

Journal Article↗

PubMed2004

Electrostatic background of chromatin fiber stretching.

We have carried out an investigation of the electrostatic forces involved in gradual removal of the DNA from the histone proteins in chromatin. Two simple models of DNA-histone core dissociation were considered. Calculations of the electrostatic free energy within the Poisson-Boltzmann theory gave similar results for the both models, which turned out to be in a qualitative agreement with recent optical tweezers stretching experiments measuring the force necessary to unwrap DNA from the histone core. Our analysis shows that the electrostatic interactions between the highly negatively charged polymeric DNA and the positively charged histones play a determining role in stabilizing the nucleosomes at physiological conditions.

Chromatin↗

PubMed2003

A molecular dynamics simulation study of oriented DNA with polyamine and sodium counterions: diffusion and averaged binding of water and cations.

Four different molecular dynamics (MD) simulations have been performed for ordered DNA decamers, d(5'-ATGCAGTCAG)*d(5'-TGACTGCATC). The counterions were the two natural polyamines spermidine3+ (Spd3+) and putrescine2+ (Put2+), the synthetic polyamine diaminopropane2+ (DAP2+) and Na+. The simulation set-up corresponds to an infinite array of parallel DNA mimicking the state in oriented DNA fibers or crystals. This work describes general properties of polyamine and Na+ binding to DNA. Simulated diffusion coefficients show satisfactory agreement with experimental NMR diffusion data of comparable systems. The interaction of the polyamines with DNA is dynamic in character and the cations mostly form short-lived contacts with the electronegative binding sites of DNA. Polyamines, Na+ and water interact most frequently with the charged phosphate atoms with preference for association from the minor groove side with O1P over O2P. There is a strong anti-correlation in the cation binding to the electronegative groups of DNA, i.e. the presence of a cation near one of the DNA sites repels other cations from binding to this and to the other sites separated by <7.5 A from each other. In contrast to the other polyamines, DAP2+ is able to form 'bridges' connecting neighboring phosphate groups along the DNA strand. A small fraction of DAP2+ and Put2+ can be found in the major grooves, while Spd3+ is absent there. The results of the MD simulations reveal principal differences in the polyamine-DNA interactions between the natural (Spd3+, Put2+ and spermine4+) and synthetic (DAP2+) polyamines.

Binding Sites↗

PubMed2003

Bead-Fourier path integral molecular dynamics.

Molecular dynamics formulation of Bead-Fourier path integral method for simulation of quantum systems at finite temperatures is presented. Within this scheme, both the bead coordinates and Fourier coefficients, defining the path representing the quantum particle, are treated as generalized coordinates with corresponding generalized momenta and masses. Introduction of the Fourier harmonics together with the center-of-mass thermostating scheme is shown to remove the ergodicity problem, known to pose serious difficulties in standard path integral molecular dynamics simulations. The method is tested for quantum harmonic oscillator and hydrogen atom (Coulombic potential). The simulation results are compared with the exact analytical solutions available for both these systems. Convergence of the results with respect to the number of beads and Fourier harmonics is analyzed. It was shown that addition of a few Fourier harmonics already improves the simulation results substantially, even for a relatively small number of beads. The proposed Bead-Fourier path integral molecular dynamics is a reliable and efficient alternative to simulations of quantum systems.

Journal Article↗

PubMed2002

Analysis of NMR J couplings in partially protected galactopyranosides.

[carbohydrate structure: see text] Hydrogen bond mediated NMR J couplings offer additional structural information. The interpretation of these usually small (h)J couplings are, however, not necessarily straightforward. In the present case of a carbohydrate system, a four-bond classical W coupling, (4)J(HO4,H5), is more reasonable on the basis of, in particular, density functional theory calculations of spin-spin coupling constants at the UB3LYP/6-311G** level of theory.

Galactose↗

PubMed2002

On the competition between water, sodium ions, and spermine in binding to DNA: a molecular dynamics computer simulation study.

The interaction of DNA with the polyamine spermine(4+) (Spm(4+)), sodium ions, and water molecules has been studied using molecular dynamics computer simulations in a system modeling a DNA crystal. The simulation model consisted of three B-DNA decamers in a periodic hexagonal cell, containing 1200 water molecules, 8 Spm(4+), 32 Na(+), and 4 Cl(-) ions. The present paper gives a more detailed account of a recently published report of this system and compares results on this mixed Spm(4+)/Na(+)-cation system with an molecular dynamics simulation carried out for the same DNA decamer under similar conditions with only sodium counterions (Korolev et al., J. Mol. Biol. 308:907). The presence of Spm(4+) makes significant influence on the DNA hydration and on the interaction of the sodium ions with DNA. Spermine pushes water molecules out of the minor groove, whereas Na(+) attracts and organizes water around DNA. The major binding site of the Spm(4+) amino groups and the Na(+) ions is the phosphate group of DNA. The flexible polyamine spermine displays a high presence in the minor groove but does not form long-lived and structurally defined complexes. Sodium ions compete with Spm(4+) for binding to the DNA bases in the minor groove. Sodium ions also have several strong binding sites in the major groove. The ability of water molecules, Spm(4+), and Na(+) to modulate the local structure of the DNA double helix is discussed.

Base Sequence↗