Showing papers by "Erik Lindahl published in 2001"

GROMACS 3.0: a package for molecular simulation and trajectory analysis

Abstract: GROMACS 3.0 is the latest release of a versatile and very well optimized package for molecular simulation. Much effort has been devoted to achieving extremely high performance on both workstations and parallel computers. The design includes an extraction of virial and periodic boundary conditions from the loops over pairwise interactions, and special software routines to enable rapid calculation of x–1/2. Inner loops are generated automatically in C or Fortran at compile time, with optimizations adapted to each architecture. Assembly loops using SSE and 3DNow! Multimedia instructions are provided for x86 processors, resulting in exceptional performance on inexpensive PC workstations. The interface is simple and easy to use (no scripting language), based on standard command line arguments with self-explanatory functionality and integrated documentation. All binary files are independent of hardware endian and can be read by versions of GROMACS compiled using different floating-point precision. A large collection of flexible tools for trajectory analysis is included, with output in the form of finished Xmgr/Grace graphs. A basic trajectory viewer is included, and several external visualization tools can read the GROMACS trajectory format. Starting with version 3.0, GROMACS is available under the GNU General Public License from http://www.gromacs.org.

Simulation of the Spontaneous Aggregation of Phospholipids into Bilayers

Abstract: The self-aggregation of lipid molecules to form bilayer membranes is a process fundamental to the organization of life. Although qualitatively explained by the hydrophobic effect, 1 the molecular aggregation itself is a complex phenomenon that has not been possible to study in detail experimentally. Here, we report a series of molecular dynamics computer simulations that for the first time demonstrate the possibility to observe the entire process at atomic detail with realistic lipids. Starting from random solutions, bilayers are formed on time scales of 10-100 ns, with properties matching experimental data. Several key steps and approximate time scales of the aggregation can be identified. The final rate-limiting process is the reduction and disappearance of large hydrophilic transmembrane water pores, of biological relevance for, for example, ion permeation. Singer and Nicholson were the first to recognize the implications of the extreme flexibility of membranes for the structure of cellular walls, leading to the famous fluid-mosaic model 2 with diffusing lipids and proteins. The bilayer formation process is, however, extremely fast and involves subtle rearrangements at the molecular level, making it elusive to current experimental methods. Simplified computer models have been used to mimic aggregation of surfactant-like molecules into monolayers and micelles, 3 bilayerlike structures, 4,5 and even vesicles. 6 These models are theoretically important to extend length and time scales, but they do not include atomic detail like hydrogen bonds and represent the collective entropic effects driving aggregation 1 as pairwise interactions. Detailed molecular dynamics simulations have on the other hand, provided accurate models of up to nanometer and nanosecond scales, but previously only for preassembled bilayers. 7-11 This work demonstrates the first simulations of aggregation of lipids into bilayers with atomic detail of the structure and interactions. Compared to micelle aggregation studies, 12,13 bilayer formation is considerably more challenging due to the balance between hydrophobicity and solvation, and the aggregation involves collective mesoscopic dynamics. The phospholipid dipalmitoylphosphatidylcholine (DPPC) was initially chosen for the study, since it is present in biological

Molecular dynamics simulation of NMR relaxation rates and slow dynamics in lipid bilayers

Abstract: By performing a 100 ns molecular dynamics simulation of a dipalmitoylphosphatidylcholine lipid bilayer we are able to calculate the full rotational correlation functions of the hydrocarbon chain C- ...

Isolated hypervariable regions derived from streptococcal M proteins specifically bind human C4b-binding protein: Implications for antigenic variation

Abstract: Antigenic variation in microbial surface proteins represents an apparent paradox, because the variable region must retain an important function, while exhibiting extensive immunological variability. We studied this problem for a group of streptococcal M proteins in which the approximately 50-residue hypervariable regions (HVRs) show essentially no residue identity but nevertheless bind the same ligand, the human complement regulator C4b-binding protein (C4BP). Synthetic peptides derived from different HVRs were found to retain the ability to bind C4BP, implying that the HVR corresponds to a distinct ligand-binding domain that can be studied in isolated form. This finding allowed direct characterization of the ligand-binding properties of isolated HVRs and permitted comparisons between different HVRs in the absence of conserved parts of the M proteins. Affinity chromatography of human serum on immobilized peptides showed that they bound C4BP with high specificity and inhibition experiments indicated that different peptides bound to the same site in C4BP. Different C4BP-binding peptides did not exhibit any immunological cross-reactivity, but structural analysis suggested that they have similar folds. These data show that the HVR of streptococcal M protein can exhibit extreme variability in sequence and immunological properties while retaining a highly specific ligand-binding function.

A direct simulation of EPR slow-motion spectra of spin labelled phospholipids in liquid crystalline bilayers based on a molecular dynamics simulation of the lipid dynamics

Abstract: EPR line shapes can be calculated from the stochastic Liouville equation assuming a stochastic model for the reorientation of the spin probe. Here we use instead and for the first time a detailed molecular dynamics (MD) simulation to generate the stochastic input to the Langevin form of the Liouville equation. A 0.1 μs MD simulation at T = 50°C of a small lipid bilayer formed by 64 dipalmitoylphosphatidylcholine (DPPC) molecules at the water content of 23 water molecules per lipid was used. In addition, a 10 ns simulation of a 16 times larger system consisting of 32 DPPC molecules with a nitroxide spin moiety attached at the sixth position of the sn2 chain and 992 ordinary DPPC molecules, was used to investigate the extent of the perturbation caused by the spin probe. Order parameters, reorientational dynamics and the EPR FID curve were calculated for spin probe molecules and ordinary DPPC molecules. The timescale of the electron spin relaxation for a spin-moiety attached at the sixth carbon position of a DPPC lipid molecule is 11.9 × 107 rad s−1 and for an unperturbed DPPC molecule it is 3.5 × 107 rad s−1.

Computational Modeling of Biological Membrane and Interface Dynamics

Abstract: The exponentially increasing power of hardware and rapid advances in numerical algorithms during the last few decades have made it possible to use computer simulations to study structure and dynamics in biomolecular systems. This thesis presents my research on biological interface dynamics, in particular lipid membranes. The studies were made possible by the development of high performance software for parallel molecular dynamics, resulting in some of the largest and longest biomolecular simulations performed to date. Calculated properties are put in relation to experimental observations, and further used to develop better theoretical models for the underlying collective dynamics. The main scientific achievements are: The lateral and normal solvent motions close to macromolecular surfaces are separated into local diffusive events on picosecond scale, and slow dynamics governed by a reduced mobility due to the potential of mean force from the surface. For the first time, undulatory & peristaltic deformations are observed in atomic detail simulations of bilayers, comprising systems of , atoms and linear scales of  nm. This makes it possible to calculate mesoscopic membrane properties like bending modulus and area compressibility in very good agreement with experiments. The theoretical framework of curvature dynamics is modified and extended. Simulated modes are consistent with macroscopic wave equations, providing a coherent model of membrane motion from . mm and  ms down to lipid sizes and  ps. The calculation of a local virial is implemented in simulations, and used to resolve pressure profiles across a bilayer. The resulting surface tension is decomposed into energetic and entropic contributions from various interactions. This provides a very detailed description of the microscopic forces keeping the bilayer together. Lipid chain nmr relaxation rates and rotational diffusion coefficients are calculated from a bilayer simulation extended to . ms, in agreement with spectroscopic results. It is further possible to determine a translational diffusion coefficient for long time scales that is consistent with values obtained by fluorescence and nmr experiments. The first-ever atomic level simulations of spontaneous aggregation of phospholipids into bilayers are reported, starting from random solutions of lipids. The aggregation is found to occur in several key steps, with the reduction and disappearance of biologically relevant transmembrane water pores as the rate limiting process.