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Interactions and dynamics in biophysical model systems
KTH, School of Engineering Sciences (SCI), Theoretical Physics. (Teoretisk Biologisk Fysik)
2009 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Computer simulations of simplified model systems provide understanding of how complex biological systems behave. The simulations give detailed information about the systems, with atomistic resolution, that can be used in combination with experimental knowledge to shed light on underlying physical principles. The thesis presents background information about the studies of two important model systems in biological physics.

First, metal ion-binding to proteins is investigated in a computational study on a zinc-binding synthetic peptide, to elucidate the binding details. The major scientific contributions from the study are the identification and mapping of the detailed contributions to the binding. A novel correction scheme is worked out, where classic free energy calculations are combined with density functional theory to adjust for quantum mechanical effects.  The sensitivity of the zinc-binding to a specific amino acid segment can be explained in terms of the zinc coordination.

Second, equilibrium density fluctuations in biological membranes are studied using computer simulations of the lipid bilayer. The fluctuations are linked to several processes; pore formation, membrane permeability and transport of small molecules across themembrane. Because the lipid bilayer behaves similar to a 2D fluid the density fluctuations can be described in the framework of generalized hydrodynamics. The major scientific contributions from the study are the direct calculation of the density-density autocorrelation function from raw data and the observation that the diffusive contribution to the power spectrum (the Rayleigh line) is not single-exponential. In addition, the accuracy of the approximate hydrodynamic solutions is questionable for the propagation of sound waves in the membrane.

Place, publisher, year, edition, pages
Stockholm: KTH , 2009. , ix, 51 p.
Series
Trita-FYS, ISSN 0280-316X ; 2009:18
National Category
Condensed Matter Physics
Identifiers
URN: urn:nbn:se:kth:diva-10300ISBN: 978-91-7415-355-2 (print)OAI: oai:DiVA.org:kth-10300DiVA: diva2:214449
Presentation
2009-05-29, FA32, Albanova Universitetscenter, Stockholm, 10:00 (English)
Opponent
Supervisors
Available from: 2009-05-18 Created: 2009-05-05 Last updated: 2010-11-03Bibliographically approved
List of papers
1. Molecular dynamics study of zinc binding to cysteines in a peptide mimic of the alcohol dehydrogenase structural zinc site
Open this publication in new window or tab >>Molecular dynamics study of zinc binding to cysteines in a peptide mimic of the alcohol dehydrogenase structural zinc site
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2009 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 11, no 6, 975-983 p.Article in journal (Refereed) Published
Abstract [en]

The binding of zinc (Zn) ions to proteins is important for many cellular events. The theoretical and computational description of this binding (as well as that of other transition metals) is a challenging task. In this paper the binding of the Zn ion to four cysteine residues in the structural site of horse liver alcohol dehydrogenase (HLADH) is studied using a synthetic peptide mimic of this site. The study includes experimental measurements of binding constants, classical free energy calculations from molecular dynamics (MD) simulations and quantum mechanical (QM) electron structure calculations. The classical MD results account for interactions at the molecular level and reproduce the absolute binding energy and the hydration free energy of the Zn ion with an accuracy of about 10%. This is insufficient to obtain correct free energy differences. QM correction terms were calculated from density functional theory (DFT) on small clusters of atoms to include electronic polarisation of the closest waters and covalent contributions to the Zn-S coordination bond. This results in reasonably good agreement with the experimentally measured binding constants and Zn ion hydration free energies in agreement with published experimental values. The study also includes the replacement of one cysteine residue to an alanine. Simulations as well as experiments showed only a small effect of this upon the binding free energy. A detailed analysis indicate that the sulfur is replaced by three water molecules, thereby changing the coordination number of Zn from four (as in the original peptide) to six (as in water).

Keyword
Alcohol Dehydrogenase, Amino Acid Sequence, Animals, Binding Sites, Biomimetic Materials, Cysteine, Horses, Liver, Models, Molecular, Molecular Conformation, Peptides, Quantum Theory, Thermodynamics, Zinc
National Category
Condensed Matter Physics
Identifiers
urn:nbn:se:kth:diva-10292 (URN)10.1039/b815482a (DOI)000262850600011 ()19177216 (PubMedID)2-s2.0-84962439482 (Scopus ID)
Note
QC 20100923Available from: 2009-05-05 Created: 2009-05-05 Last updated: 2010-09-23Bibliographically approved
2. Dynamic structure factors from lipid membrane molecular dynamics simulations
Open this publication in new window or tab >>Dynamic structure factors from lipid membrane molecular dynamics simulations
2009 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 96, no 5, 1828-1838 p.Article in journal (Refereed) Published
Abstract [en]

Dynamic structure factors for a lipid bilayer have been calculated from molecular dynamics simulations. From trajectories of a system containing 1024 lipids we obtain wave vectors down to 0.34 nm(-1), which enables us to directly resolve the Rayleigh and Brillouin lines of the spectrum. The results confirm the validity of a model based on generalized hydrodynamics, but also improves the line widths and the position of the Brillouin lines. The improved resolution shows that the Rayleigh line is narrower than in earlier studies, which corresponds to a smaller thermal diffusivity. From a detailed analysis of the power spectrum, we can, in fact, distinguish two dispersive contributions to the elastic scattering. These translate to two exponential relaxation processes in separate time domains. Further, by including a first correction to the wave-vector-dependent position of the Brillouin lines, the results agree favorably to generalized hydrodynamics even up to intermediate wave vectors, and also yields a 20% higher adiabatic sound velocity. The width of the Brillouin lines shows a linear, not quadratic, dependence to low wave vectors.

Keyword
X-RAY-SCATTERING, LENNARD-JONES LIQUID, PARTICLE MESH EWALD, NEUTRON-SCATTERING, DENSITY-FLUCTUATIONS, COMPUTER EXPERIMENTS, CLASSICAL FLUIDS, BRILLOUIN-SCATTERING, COLLECTIVE DYNAMICS, CONSTANT-PRESSURE
National Category
Condensed Matter Physics
Identifiers
urn:nbn:se:kth:diva-10294 (URN)10.1016/j.bpj.2008.11.044 (DOI)000266376500014 ()19254541 (PubMedID)2-s2.0-65549120360 (Scopus ID)
Note
QC 20101006Available from: 2009-05-05 Created: 2009-05-05 Last updated: 2011-10-14Bibliographically approved

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