Biomedical subjects

L Cruzeiro-Hansson

Publications and source records attributed to L Cruzeiro-Hansson.

6 recordsLinked to original sources

PubMed1994

Adenine.methylthymine base-pairs enhance non-uniformity in DNA helices.

Nitroso compounds are known to induce mutations and cancer. Here we study the effect of methylation of O4 of thymine by nitroso compounds on the structure and dynamics of DNA helices. Four dodecamers, for which there exist experimental data obtained by NMR techniques, are studied using very long (approximately 1 ns) molecular dynamics simulations. The conformations obtained are in good agreement with the NMR data. A statistical analysis indicates that DNA in solution adopts conformations which are intermediate between those of the ideal DNA families, such as A and B-DNA. Also, the structures obtained in these molecular dynamics simulations possess a greater degree of non-uniformity than the crystal structures. Most importantly, the helices containing adenine.methylthymine base-pairs show a further enhancement in non-uniformity. A biological role for the enhanced nonuniformity is suggested.

Adenine↗

PubMed1994

DNA structure, hydration and dynamics.

Although the double helical model of DNA structure is now 40 years old, there is still considerable effort being made to elucidate the range of conformations that can be adopted by this flexible molecule. We review the current state of our knowledge of DNA structure which is available from both experimental and computational approaches.

DNA↗

PubMed1994

Flexibility and curvature of DNA duplexes containing O4-methylthymine: implications for DNA repair.

Nitroso compounds are known to induce mutations and cancer. We study the effect of one of their products, O4-methylthymine, on the structure and flexibility of DNA sequences. In particular, we focus on aspects of DNA that are relevant for the interaction with the repair protein, O6-alkylguanine-DNA alkyltransferase. In general, sequences that contain O4-methylthymine have greater local curvatures. Sequences in which O4-methylthymine is paired with adenine have larger regions of increased flexibility, a consistent bend in the direction of the major groove and strong oscillations in the major groove widths. On the other hand, sequences in which O4-methylthymine is paired with guanine have only sites of increased flexibility, short regions bent towards the major groove alternating with sites bent toward the minor groove and larger major groove widths than those of canonical B-DNA. These features may possibly lead to the difference in the efficiency with which repair proteins correct the lesions in the two base pairs. Further experimental data are needed to make more definitive conclusions.

Alkylation↗

PubMed1992

Molecular dynamics of alkylated DNA.

The effect of methylation of the O4 atom of thymine in two oligonucleotide sequences is investigated by molecular dynamics simulations. Three types of environments are considered including: (i) in vacuo calculation, with a distance-dependent dielectric function and unhydrated counter-ions; (ii) in vacuo calculation, with a distance-dependent dielectric constant and hydrated counter-ions; and (iii) with a 9 A thick explicit water layer and counter-ions. In all environments, the oligonucleotide sequence containing the chemically modified thymine paired with guanine is more stable than the oligonucleotide sequence in which the modified thymine is paired with adenine. The methyl group attached to the O4 atom of thymine is found in a syn configuration with respect to the N3 atom. The best fit between the experimental NMR results and the molecular dynamics simulations is obtained using the environment with hydrated counter-ions.

Alkylation↗

PubMed1989

Intrinsic molecules in lipid membranes change the lipid-domain interfacial area: cholesterol at domain interfaces.

A theoretical analysis of the effects of intrinsic molecules on the lateral density fluctuations in lipid bilayer membranes is carried out by means of computer simulations on a microscopic interaction model of the gel-to-fluid chain-melting phase transition. The inhomogeneous equilibrium structures of gel and fluid domains, which in previous work (Cruzeiro-Hansson, L. and Mouritsen, O.G. (1988) Biochim. Biophys. Acta 944, 63-72) were shown to characterize the transition region of pure lipid membranes, are here shown to be enhanced by intrinsic molecules such as cholesterol. Cholesterol is found to increase the interfacial area and to accumulate in the interfaces. The interfacial area, the average cluster size, the lateral compressibility, and the membrane area are calculated as functions of temperature and cholesterol concentration. It is shown that the enhancement by cholesterol of the lateral density fluctuations and the lipid-domain interfacial area is most pronounced away from the transition temperature. The implications of the results are discussed in relation to passive ion permeability and function of interfacially active enzymes such as phospholipase.

Cell Membrane Permeability↗

PubMed1988

Passive ion permeability of lipid membranes modelled via lipid-domain interfacial area.

A microscopic interaction model of the gel-to-fluid chain-melting phase transition of fully hydrated lipid bilayer membranes is used as a basis for modelling the temperature dependence of passive transmembrane permeability of small ions, e.g. Na+. Computer simulation of the model shows that the phase transition is accompanied by strong lateral density fluctuations which manifest themselves in the formation of inhomogeneous equilibrium structures of coexisting gel and fluid domains. The interfaces of these domains are found to be dominated by intermediate lipid-chain conformations. The interfacial area is shown to have a pronounced peak at the phase transition. By imposing a simple model for ion diffusion through membranes which assigns a high relative permeation rate to the domain interfaces, the interfacial area is then identified as a membrane property which has the proper temperature variation to account for the peculiar experimental observation of a strongly enhanced passive ion permeability at the phase transition. The excellent agreement with the experimental data for Na+-permeation, taken together with recent experimental results for the phase transition kinetics, provides new insight into the microphysical mechanisms of reversible electric breakdown. This insight indicates that there is no need for aqueous pore-formation to explain the experimental observation of a dramatic increase in ion conductance subsequent to electric pulses.

Algorithms↗