| 1. |
- Jämbeck, Joakim P. M., 1986-, et al.
(författare)
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An extension and further validation of an all atomistic force field for biological membranes
- 2012
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 8:8, s. 2938-2948
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Tidskriftsartikel (refereegranskat)abstract
- Biological membranes are versatile in composition and host intriguing molecular processes. In order to be able to study these systems, an accurate model Hamiltonian or force field (FF) is a necessity. Here, we report the results of our extension of earlier developed all-atomistic FF parameters for fully saturated phospholipids that complements an earlier parameter set for saturated phosphatidylcholine lipids (J. Phys. Chem. B, 2012, 116, 3164-3179). The FF, coined Slipids (Stockholm lipids), now also includes parameters for unsaturated phosphatidylcholine and phosphatidylethanolamine lipids, e.g., POPC, DOPC, SOPC, POPE, and DOPE. As the extended set of parameters is derived with the same philosophy as previously applied, the resulting FF has been developed in a fully consistent manner. The capabilities of Slipids are demonstrated by performing long simulations without applying any surface tension and using the correct isothermal-isobaric (NPT) ensemble for a range of temperatures and carefully comparing a number of properties with experimental findings. Results show that several structural properties are very well reproduced, such as scattering form factors, NMR order parameters, thicknesses, and area per lipid. Thermal dependencies of different thicknesses and area per lipid are reproduced as well Lipid diffusion is systematically slightly underestimated, whereas the normalized lipid diffusion follows the experimental trends. This is believed to be due to the lack of collective movement in the relatively small bilayer patches used Furthermore, the compatibility with amino acid FFs from the AMBER family is tested in explicit transmembrane complexes of the WALP23 peptide with DLPC and DOPC bilayers, and this shows that Slipids can be used to study more complex and biologically relevant systems.
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| 2. |
- Jämbeck, Joakim P. M., 1986-, et al.
(författare)
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Another piece of the membrane puzzle : extending slipids further
- 2013
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 9:1, s. 774-784
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Tidskriftsartikel (refereegranskat)abstract
- To be able to model complex biological membranes in a more realistic manner, the force field Slipids (Stockholm lipids) has been extended to include parameters for sphingomyelin (SM), phosphatidylglycerol (PG), phosphatidylserine (PS) lipids, and cholesterol. Since the parametrization scheme was faithful to the scheme used in previous editions of Slipids, all parameters are consistent and fully compatible. The results of careful validation of a number of key structural properties for one and two component lipid bilayers are in excellent agreement with experiments. Potentials of mean force for transferring water across binary mixtures of lipids and cholesterol were also computed in order to compare water permeability rates to experiments. In agreement with experimental and simulation studies, it was found that the permeability and partitioning of water is affected by cholesterol in lipid bilayers made of saturated lipids to the largest extent. With the extensions of Slipids presented here, it is now possible to study complex systems containing many different lipids and proteins in a fully atomistic resolution in the isothermic-isobaric (NPT) ensemble, which is the proper ensemble for membrane simulations.
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| 3. |
- Jämbeck, Joakim P. M., 1986-
(författare)
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Computer Simulations of Heterogenous Biomembranes
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Molecular modeling has come a long way during the past decades and in the current thesis modeling of biological membranes is the focus. The main method of choice has been classical Molecular Dynamics simulations and for this technique a model Hamiltonian, or force field (FF), has been developed for lipids to be used for biological membranes. Further, ways of more accurately simulate the interactions between solutes and membranes have been investigated.A FF coined Slipids was developed and validated against a range of experimental data (Papers I-III). Several structural properties such as area per lipid, scattering form factors and NMR order parameters obtained from the simulations are in good agreement with available experimental data. Further, the compatibility of Slipids with amino acid FFs was proven. This, together with the wide range of lipids that can be studied, makes Slipids an ideal candidate for large-scale studies of biologically relevant systems.A solute's electron distribution is changed as it is transferred from water to a bilayer, a phenomena that cannot be fully captured with fixed-charge FFs. In Paper IV we propose a scheme of implicitly including these effects with fixed-charge FFs in order to more realistically model water-membrane partitioning. The results are in good agreement with experiments in terms of free energies and further the differences between using this scheme and the more traditional approach were highlighted.The free energy landscape (FEL) of solutes embedded in a model membrane is explored in Paper V. This was done using biased sampling methods with a reaction coordinate that included intramolecular degrees of freedom (DoF). These DoFs were identified in different bulk liquids and then used in studies with bilayers. The FELs describe the conformational changes necessary for the system to follow the lowest free energy path. Besides this, the pitfalls of using a one-dimensional reaction coordinate are highlighted.
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| 4. |
- Jämbeck, Joakim P. M., 1986-, et al.
(författare)
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Derivation and Systematic Validation of a Refined All-Atom Force Field for Phosphatidylcholine Lipids
- 2012
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 116:10, s. 3164-3179
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Tidskriftsartikel (refereegranskat)abstract
- An all-atomistic force field (FF) has been developed for fully saturated phospholipids. The parametrization has been largely based on high-level ab initio calculations in order to keep the empirical input to a minimum. Parameters for the lipid chains have been developed based on knowledge about bulk alkane liquids, for which thermodynamic and dynamic data are excellently reproduced. The FFs ability to simulate lipid bilayers in the liquid crystalline phase in a tensionless ensemble was tested in simulations of three lipids: 1,2-diauroyl-sn-glycero-3-phospocholine (DLPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), and 1,2-dipalmitoyl-sn-glycero-3-phospcholine (DPPC). Computed areas and volumes per lipid, and three different kinds of bilayer thicknesses, have been investigated. Most importantly NMR order parameters and scattering form factors agree in an excellent manner with experimental data under a range of temperatures. Further, the compatibility with the AMBER FF for biomolecules as well as the ability to simulate bilayers in gel phase was demonstrated. Overall, the FF presented here provides the important balance between the hydrophilic and hydrophobic forces present in lipid bilayers and therefore can be used for more complicated studies of realistic biological membranes with protein insertions.
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| 5. |
- Jämbeck, Joakim P. M., 1986-, et al.
(författare)
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Exploring the Free Energy Landscape of Solutes Embedded in Lipid Bilayers
- 2013
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Ingår i: The Journal of Physical Chemistry Letters. - : American Chemical Society (ACS). - 1948-7185. ; 4:11, s. 1781-1787
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Tidskriftsartikel (refereegranskat)abstract
- Free energy calculations are vital for our understanding of biological processes on an atomistic scale and can offer insight to various mechanisms. However, in some cases, degrees of freedom (DOFs) orthogonal to the reaction coordinate have high energy barriers and/or long equilibration times, which prohibit proper sampling. Here we identify these orthogonal DOFs when studying the transfer of a solute from water to a model membrane. Important DOFs are identified in bulk liquids of different dielectric nature with metadynamics simulations and are used as reaction coordinates for the translocation process, resulting in two- and three-dimensional space of reaction coordinates. The results are in good agreement with experiments and elucidate the pitfalls of using one-dimensional reaction coordinates. The calculations performed here offer the most detailed free energy landscape of solutes embedded in lipid bilayers to date and show that free energy calculations can be used to study complex membrane translocation phenomena.
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| 6. |
- Jämbeck, Joakim P. M., 1986-, et al.
(författare)
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Implicit inclusion of atomic polarization in modeling of partitioning between water and lipid bilayers
- 2013
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 15:13, s. 4677-4686
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Tidskriftsartikel (refereegranskat)abstract
- We propose an effective and straightforward way of including atomic polarization in simulations of the partitioning of small molecules in inhomogenous media based on classical molecular dynamics with non-polarizable force fields. The approach presented here takes advantage of the relatively fast sampling of phase space obtained with additive force fields by adding the polarization effects afterwards. By using pre-polarized charges for the polar and non-polar phases together with a polarization correction term the effects of atomic polarization are effectively taken into account. The results show a clear improvement compared to using the more common setup with one set of charges obtained from gas phase ab initio calculations. It is shown that when proper measures are taken into account computer simulations with non-polarizable force fields are able to accurately determine water-membrane partitioning and preferential location of small molecules in the membrane interior. We believe that the approach presented here can be useful in rational drug design and in investigations of molecular mechanisms of anesthetic or toxic action.
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| 7. |
- Jämbeck, Joakim P. M., 1986-, et al.
(författare)
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Molecular Dynamics Studies of Liposomes as Carriers for Photosensitizing Drugs : Development, Validation, and Simulations with a Coarse-Grained Model
- 2014
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 10:1, s. 5-13
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Tidskriftsartikel (refereegranskat)abstract
- Liposomes are proposed as drug delivery systems and can in principle be designed so as to cohere with specific tissue types or local environments. However, little detail is known about the exact mechanisms for drug delivery and the distributions of drug molecules inside the lipid carrier. In the current work, a coarse-grained (CG) liposome model is developed, consisting of over 2500 lipids, with varying degrees of drug loading. For the drug molecule, we chose hypericin, a natural compound proposed for use in photodynamic therapy, for which a CG model was derived and benchmarked against corresponding atomistic membrane bilayer model simulations. Liposomes with 21-84 hypericin molecules were generated and subjected to 10 microsecond simulations. Distribution of the hypericins, their orientations within the lipid bilayer, and the potential of mean force for transferring a hypericin molecule from the interior aqueous droplet through the liposome bilayer are reported herein.
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| 8. |
- Jämbeck, Joakim P. M., 1986-, et al.
(författare)
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Partial Atomic Charges and Their Impact on the Free Energy of Solvation
- 2013
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Ingår i: Journal of Computational Chemistry. - : Wiley. - 0192-8651 .- 1096-987X. ; 34:3, s. 187-197
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Tidskriftsartikel (refereegranskat)abstract
- Free energies of solvation (Delta G) in water and n-octanol have been computed for common drug molecules by molecular dynamics simulations with an additive fixed-charge force field. The impact of the electrostatic interactions was investigated by computing the partial atomic charges with four methods that all fit the charges from the quantum mechanically determined electrostatic potential (ESP). Due to the redistribution of electron density that occurs when molecules are transferred from gas phase to condensed phase, the polarization impact was also investigated. By computing the partial atomic charges with the solutes placed in a conductor-like continuum, the charges were effectively polarized to take the polarization effects into account. No polarization correction term or similar was considered, only the partial atomic charges. Results show that free energies are very sensitive to the choice of atomic charges and that Delta G can differ by several k(B)T depending on the charge computing method. Inclusion of polarization effects makes the solutes too hydrophilic with most methods and in vacuo charges make the solutes too hydrophobic. The restrained-ESP methods together with effectively polarized charges perform well in our test set and also when applied to a larger set of molecules. The effect of water models is also highlighted and shows that the conclusions drawn are valid for different three-point models. Partitioning between an aqueous and a hydrophobic phase is also described better if the two environment's polarization is taken into account, but again the results are sensitive to the charge calculation method. Overall, the results presented here show that effectively polarized charges can improve the description of solvating a drug-like molecule in a solvent and that the choice of partial atomic charges is crucial to ensure that molecular simulations produce reliable results.
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