arXiv subjects

N. V. Dokholyan

Publications and source records attributed to N. V. Dokholyan.

4 recordsLinked to original sources

arXiv2004

Molecular Dynamics Simulation of Amyloid Beta Dimer Formation

Recent experiments with amyloid-beta (Abeta) peptide suggest that formation of toxic oligomers may be an important contribution to the onset of Alzheimer's disease. The toxicity of Abeta oligomers depends on their structure, which is governed by assembly dynamics. Due to limitations of current experimental techniques, a detailed knowledge of oligomer structure at the atomic level is missing. We introduce a molecular dynamics approach to study Abeta dimer formation: (1) we use discrete molecular dynamics simulations of a coarse-grained model to identify a variety of dimer conformations, and (2) we employ all-atom molecular mechanics simulations to estimate the thermodynamic stability of all dimer conformations. Our simulations of a coarse-grained Abeta peptide model predicts ten different planar beta-strand dimer conformations. We then estimate the free energies of all dimer conformations in all-atom molecular mechanics simulations with explicit water. We compare the free energies of Abeta(1-42) and Abeta(1-40) dimers. We find that (a) all dimer conformations have higher free energies compared to their corresponding monomeric states, and (b) the free energy difference between the Abeta(1-42) and the analogous Abeta(1-40) dimer conformation is not significant. Our results suggest that Abeta oligomerization is not accompanied by the formation of stable planar beta-strand Abeta dimers.

physics.bio-ph↗

arXiv2003

Discrete molecular dynamics simulations of peptide aggregation

We study the aggregation of peptides using the discrete molecular dynamics simulations. At temperatures above the alpha-helix melting temperature of a single peptide, the model peptides aggregate into a multi-layer parallel beta-sheet structure. This structure has an inter-strand distance of 0.48 nm and an inter-sheet distance of 1.0 nm, which agree with experimental observations. In this model, the hydrogen bond interactions give rise to the inter-strand spacing in beta-sheets, while the Go interactions among side chains make beta-strands parallel to each other and allow beta-sheets to pack into layers. The aggregates also contain free edges which may allow for further aggregation of model peptides to form elongated fibrils.

cond-mat.soft↗

arXiv2003

Multiple Folding Pathways of the SH3 domain

Experimental observations suggest that proteins follow different pathways under different environmental conditions. We perform molecular dynamics simulations of a model of the SH3 domain over a broad range of temperatures, and identify distinct pathways in the folding transition. We determine the kinetic partition temperature --the temperature for which the SH3 domain undergoes a rapid folding transition with minimal kinetic barriers-- and observe that below this temperature the model protein may undergo a folding transition via multiple folding pathways. The folding kinetics is characterized by slow and fast pathways and the presence of only one or two intermediates. Our findings suggest the hypothesis that the SH3 domain, a protein for which only two-state folding kinetics was observed in previous experiments, may exhibit intermediates states under extreme experimental conditions, such as very low temperatures. A very recent report (Viguera et al., Proc. Natl. Acad. Sci. USA, 100:5730--5735, 2003) of an intermediate in the folding transition of the Bergerac mutant of the alpha-spectrin SH3 domain protein supports this hypothesis.

physics.bio-ph↗

arXiv2000

Hierarchical organization of cities and nations

Universality in the behavior of complex systems often reveals itself in the form of scale-invariant distributions that are essentially independent of the details of the microscopic dynamics. A representative paradigm of complex behavior in nature is cooperative evolution. The interaction of individuals gives rise to a wide variety of collective phenomena that strongly differ from individual dynamics---such as demographic evolution, cultural and technological development, and economic activity. A striking example of such cooperative phenomena is the formation of urban aggregates which, in turn, can be considered to cooperate in giving rise to nations. We find that population and area distributions of nations follow an inverse power-law behavior, as is known for cities. The exponents, however, are radically different in the two cases ($μ\approx 1$ for nations, $μ\approx 2$ for cities). We interpret these findings by developing growth models for cities and for nations related to basic properties of partition of the plane. These models allow one to understand the empirical findings without resort to the introduction of complex socio-economic factors.

cond-mat.stat-mech↗