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Classical and Quantum Descriptions of Proteins, Lipids and Membranes
KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical Biological Physics.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis the properties of proteins and membranes are studied by molecular dynamics simulations. The subject is decomposed into parts addressing free energy calculations in proteins, mechanical inclusion models for lipid bilayers, phase transitions and structural correlations in lipid bilayers and atomistic lipid bilayer models. The work is based on results from large scale computer simulations, quantum mechanical and continuum models. Efficient statistical sampling and the coarseness of the models needed to describe the ordered and disordered states are of central concern.

Classical free energy calculations of zinc binding, in metalloproteins, require a quantum mechanical correction in order to obtain realistic binding energies. Classical electrostatic polarisation will influence the binding energy in a large region surrounding the ion and produce reasonable equilibrium structures in the bound state, when compared to experimental evidence.

The free energy for inserting a protein into a membrane is calculated with continuum theory. The free energy is assumed quadratic in the mismatch and depend on two elastic constants of the membrane. Under these circumstances, the free energy can then be written as a line tension multiplied by the circumference of the membrane inclusion. The inclusion model and coarse grained particle simulations of the membranes show that the thickness profile around the protein will be an exponentially damped oscillation.

Coarse-grained particle simulations of model membranes containing mixtures of phospholipid and cholesterol molecules at different conditions were performed. The gel-to-liquid crystalline phase transition is successively weakened with increasing amounts of cholesterol without disappearing even at a concentration of cholesterol as high as 60%.

A united atom parameterization of diacyl lipids was constructed. The aim was to construct a new force field that retains and improves the good agreement for the fluid phase and at the same time produces a gel phase at low temperatures, with properties coherent with experimental findings. The global bilayer tilt obtains an azimuthal value of 31and is aligned between lattice vectors in the bilayer plane. It is also shown that the model yield a correct heat of melting as well as heat capacities in the fluid and gel phase of DPPC.

 

Place, publisher, year, edition, pages
Stockholm, Sweden: KTH Royal Institute of Technology, 2014. , xiv, 73 p.
Series
TRITA-FYS, ISSN 0280-316X ; 2014:55
Keyword [en]
Quantum corrections, Coordination structure, Polarisation, Phase transitions, Kelvin differential equation, Line tension, Elastic membrane models, Molecular particle models, Zinc binding, Cholesterol and Phospholipids
National Category
Physical Sciences
Research subject
Biological Physics
Identifiers
URN: urn:nbn:se:kth:diva-151396ISBN: 978-91-7595-253-6 (print)OAI: oai:DiVA.org:kth-151396DiVA: diva2:748464
Public defence
2014-10-03, Sal FA32, AlbaNova Universitetscentrum, Roslagstullsbacken 21, Stockholm, 10:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council
Note

QC 20140919

Available from: 2014-09-19 Created: 2014-09-19 Last updated: 2014-10-07Bibliographically approved
List of papers
1. Molecular dynamics simulations of Zn2+ coordination in protein binding sites
Open this publication in new window or tab >>Molecular dynamics simulations of Zn2+ coordination in protein binding sites
2010 (English)In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 132, no 20, 205101- p.Article in journal (Refereed) Published
Abstract [en]

A systematic molecular dynamics (MD) study of zinc binding to a peptide that mimics the structural binding site of horse liver alcohol dehydrogenase (HLADH) has been conducted. The four zinc binding cysteines were successively mutated into alanines to study the stability, zinc coordination, and free energy of binding. The zinc ion is coordinated to four sulfurs in the native peptide as in x-ray structures of HLADH. When the cysteines are replaced by alanines, the zinc coordinating sulfurs are replaced by waters and/or polypeptide backbone carbonyl oxygens. With two or fewer cysteines, the coordination number increases from four to six, while the coordination number varies between four and six with three cysteines depending on which of the cysteines that is replaced by an alanine. The binding free energies of zinc to the proteins were calculated from MD free energy integration runs to which corrections from quantum mechanical cluster calculations were added. There is a reasonable correlation with experimental binding free energies [T. Bergman , Cell. Mol. Life Sci. 65, 4019 (2008)]. For the chains with the lowest structural fluctuations and highest free energies lower coordination numbers for zinc are obtained. Finally, x-ray absorption fine structure spectra were calculated from the MD structures.

Keyword
binding energy, coupled cluster calculations, EXAFS, molecular dynamics method, proteins, zinc
National Category
Physical Sciences
Identifiers
urn:nbn:se:kth:diva-27544 (URN)10.1063/1.3428381 (DOI)000278183100033 ()2-s2.0-77953075511 (Scopus ID)
Funder
Swedish Research Council
Note
QC 20101217Available from: 2010-12-17 Created: 2010-12-13 Last updated: 2017-12-11Bibliographically approved
2. Phase Transitions in Coarse-Grained Lipid Bilayers Containing Cholesterol by Molecular Dynamics Simulations
Open this publication in new window or tab >>Phase Transitions in Coarse-Grained Lipid Bilayers Containing Cholesterol by Molecular Dynamics Simulations
2012 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 103, no 10, 2125-2133 p.Article in journal (Refereed) Published
Abstract [en]

Coarse-grained simulations of model membranes containing mixtures of phospholipid and cholesterol molecules at different concentrations and temperatures have been performed. A random mixing without tendencies for segregation or formation of domains was observed on spatial scales corresponding to a few thousand lipids and timescales up to several micro-seconds. The gel-to-liquid crystalline phase transition is successively weakened with increasing amounts of cholesterol without disappearing completely even at a concentration of cholesterol as high as 60%. The phase transition temperature increases slightly depending on the cholesterol concentration. The gel phase system undergoes a transition with increasing amounts of cholesterol from a solid-ordered phase into a liquid-ordered one. In the solid phase, the amplitude of the oscillations in the radial distribution function decays algebraically with a prefactor that goes to zero at the solid-liquid transition.

Keyword
particle mesh ewald, liquid water, model, tip4p/2005, spectra, range
National Category
Physical Chemistry
Identifiers
urn:nbn:se:kth:diva-102277 (URN)10.1016/j.bpj.2012.10.014 (DOI)000311419000011 ()2-s2.0-84869465857 (Scopus ID)
Funder
Swedish Research CouncilSwedish e‐Science Research Center
Note

QC 20130107. Updated from accepted to published.

Available from: 2012-09-12 Created: 2012-09-12 Last updated: 2017-12-07Bibliographically approved
3. The shape and free energy of a lipid bilayer surrounding a membrane inclusion
Open this publication in new window or tab >>The shape and free energy of a lipid bilayer surrounding a membrane inclusion
2013 (English)In: Chemistry and Physics of Lipids, ISSN 0009-3084, E-ISSN 1873-2941, Vol. 169, 2-8 p.Article in journal (Refereed) Published
Abstract [en]

Membrane inclusion interactions are studied within the scope of continuum theory. We show that the free energy functional for the membrane thickness can be rewritten as a constant times a dimensionless integral. For cylindrical inclusions, the resulting differential equation gives a thickness profile that depends on the radius of the cylinder and one single lipid property, a correlation length that is determined by the ratio of the thickness compressibility and bending moduli. The solutions decay in a non-monotonic fashion with one single observable minimum. A solution for planar geometry may either be explicitly constructed or obtained by letting the radius of the cylinder go to infinity. In dimensionless units the initial derivative of the thickness profile is universal and equal to -1/root 2 In physical units, the derivative depends on the size of the hydrophobic mismatch as well as the membrane correlation length and will usually be fairly small but clearly non-zero. The line tension between the protein inclusion and a fluid phase membrane will depend on the hydrophobic mismatch and be of the order of 10 pN (larger for the gel phase). This results in free energy costs for the inclusion that will be up to tens of kJ/mol (in the fluid phase).

Keyword
Membrane protein interactions, Continuum theory, Line tension, Kelvin functions, Coarse graining, Molecular dynamics
National Category
Physical Chemistry
Identifiers
urn:nbn:se:kth:diva-124470 (URN)10.1016/j.chemphyslip.2012.12.005 (DOI)000319310800002 ()2-s2.0-84876420080 (Scopus ID)
Note

QC 20130708

Available from: 2013-07-08 Created: 2013-07-05 Last updated: 2017-12-06Bibliographically approved
4. Reparameterized united atom model for molecular dynamics simulations of gel and fluid phosphatidylcholine bilayers
Open this publication in new window or tab >>Reparameterized united atom model for molecular dynamics simulations of gel and fluid phosphatidylcholine bilayers
2014 (English)In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 10, no 12, 5706-5715 p.Article in journal (Refereed) Published
Abstract [en]

A new united atom parametrization of diacyl lipids like dipalmitoylphosphatidylcholine (DPPC) and the dimyristoylphosphatidylcholine (DMPC) has been constructed based on ab initio calculations to obtain fractional charges and the dihedral potential of the hydrocarbon chains, while the Lennard-Jones parameters of the acyl chains were fitted to reproduce the properties of liquid hydrocarbons. The results have been validated against published experimental X-ray and neutron scattering data for fluid and gel phase DPPC. The derived charges of the lipid phosphatidylcholine (PC) headgroup are shown to yield dipole components in the range suggested by experiments. The aim has been to construct a new force field that retains and improves the good agreement for the fluid phase and at the same time produces a gel phase at low temperatures, with properties coherent with experimental findings. The gel phase of diacyl-PC lipids forms a regular triangular lattice in the hydrocarbon region. The global bilayer tilt obtains an azimuthal value of 31 degrees and is aligned between lattice vectors in the bilayer plane. We also show that the model yields a correct heat of melting as well as decent heat capacities in the fluid and gel phase of DPPC.

National Category
Physical Sciences
Research subject
Biological Physics
Identifiers
urn:nbn:se:kth:diva-151393 (URN)10.1021/ct500589z (DOI)000346324000052 ()2-s2.0-84916613010 (Scopus ID)
Funder
Swedish Research Council
Note

QC 20150220. Updates from submitted to published. Previous title "A Re-parameterized United Atom Model for Molecular Dynamics Simulations of Gel and Fluid Phosphatidylcholine Bilayers".

Available from: 2014-09-19 Created: 2014-09-19 Last updated: 2017-12-05Bibliographically approved

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