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Protein folding kinetics and thermodynamics from atomistic simulations
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.
2006 (English)In: Physical Review Letters, ISSN 0031-9007, E-ISSN 1079-7114, Vol. 96, no 23, 238102- p.Article in journal (Refereed) Published
Abstract [en]

Determining protein folding kinetics and thermodynamics from all-atom molecular dynamics (MD) simulations without using experimental data represents a formidable scientific challenge because simulations can easily get trapped in local minima on rough free energy landscapes. This necessitates the computation of multiple simulation trajectories, which can be independent from each other or coupled in some manner, as, for example, in the replica exchange MD method. Here we present results obtained with a new analysis tool that allows the deduction of faithful kinetics data from a heterogeneous ensemble of simulation trajectories. The method is demonstrated on the decapeptide Chignolin for which we predict folding and unfolding time constants of 1.0±0.3 and 2.6±0.4  μs, respectively. We also derive the energetics of folding, and calculate a realistic melting curve for Chignolin.

Place, publisher, year, edition, pages
2006. Vol. 96, no 23, 238102- p.
Keyword [en]
Computer Simulation, Kinetics, Models; Chemical, Models; Molecular, Protein Folding, Proteins/*chemistry/*ultrastructure, Quantum Theory, Research Support; Non-U.S. Gov't, Thermodynamics
National Category
Bioinformatics and Systems Biology
URN: urn:nbn:se:uu:diva-18880DOI: 10.1103/PhysRevLett.96.238102PubMedID: 16803409OAI: oai:DiVA.org:uu-18880DiVA: diva2:46652
Available from: 2006-11-23 Created: 2006-11-23 Last updated: 2014-10-29Bibliographically approved
In thesis
1. Protein Folding and DNA Origami
Open this publication in new window or tab >>Protein Folding and DNA Origami
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis, the folding process of the de novo designed polypeptide chignolin was elucidated through atomic-scale Molecular Dynamics (MD) computer simulations. In a series of long timescale and replica exchange MD simulations, chignolin’s folding and unfolding was observed numerous times and the native state was identified from the computed Gibbs free-energy landscape. The rate of the self-assembly process was predicted from the replica exchange data through a novel algorithm and the structural fluctuations of an enzyme, lysozyme, were analyzed.

DNA’s structural flexibility was investigated through experimental structure determination methods in the liquid and gas phase. DNA nanostructures could be maintained in a flat geometry when attached to an electrostatically charged, atomically flat surface and imaged in solution with an Atomic Force Microscope. Free in solution under otherwise identical conditions, the origami exhibited substantial compaction, as revealed by small angle X-ray scattering. This condensation was even more extensive in the gas phase.

Protein folding is highly reproducible. It can rapidly lead to a stable state, which undergoes moderate fluctuations, at least for small structures. DNA maintains extensive structural flexibility, even when folded into large DNA origami.

One may reflect upon the functional roles of proteins and DNA as a consequence of their atomic-level structural flexibility. DNA, biology’s information carrier, is very flexible and malleable, adopting to ever new conformations. Proteins, nature’s machines, faithfully adopt highly reproducible shapes to perform life’s functions robotically.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 43 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 724
protein folding, Molecular Dynamics simulations, DNA origami
National Category
Research subject
Physics with specialization in Biophysics
urn:nbn:se:uu:diva-121549 (URN)978-91-554-7756-1 (ISBN)
Public defence
2010-04-20, B21, Husargatan 3, 751 24 Uppsala, BMC, 10:15 (English)
Available from: 2010-03-29 Created: 2010-03-25 Last updated: 2011-03-04

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