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J Aqvist

Publications and source records attributed to J Aqvist.

46 records · Page 3Linked to original sources
PubMed1989

A molecular dynamics study of the C-terminal fragment of the L7/L12 ribosomal protein. II. Effects of intermolecular interactions on structure and dynamics.

The crystallographic dimer of the C-terminal fragment (CTF) of the L7/L12 ribosomal protein has been subjected to molecular dynamics (MD) simulations. A 90 picosecond (ps) trajectory for the protein dimer, 19 water molecules and two counter ions has been calculated at constant temperature. Effects of intermolecular interactions on the structure and dynamics have been studied. The exact crystallographic symmetry is lost and the atomic fluctuations differ from one monomer to the other. The average MD structure is more stable than the X-ray one, as judged by accessible surface area and energy calculations. Crystal (non-dimeric) interactions have been simulated in another 40 ps trajectory by using harmonic restraints to represent intermolecular hydrogen bonds. The conformational changes with respect to the X-ray structure are then virtually suppressed. The unrestrained dimer trajectory has been scanned for cooperative motions involving secondary structure elements. The intrinsic collective motions of the monomer are transmitted via intermolecular contacts to the dimer structure. The existence of a stable dimeric form of CTF, resembling the crystallographic one, has been documented. At the cost of fairly small energy expenditure the dimer has considerable conformational flexibility. This flexibility may endow the dimer with some functional potential as an energy transducer.

Computer Simulation↗
PubMed1989

Energetics of ion permeation through membrane channels. Solvation of Na+ by gramicidin A.

Calculations of the solvation energetics for a Na+ ion inside the Gramicidin A channel and in water are presented. The protein dipoles Langevin dipoles (PDLD) method is used to obtain an electrostatic free energy profile for ion permeation through the channel. To gauge the quality of the PDLD results the solvation free energy of a Na+ ion in water and in the center of the channel is also calculated using free energy perturbation (FEP) simulations. The effect of the polarisability of the surrounding lipid membrane is taken into account by representing the membrane by a large grid of polarisable point dipoles. The two methods give similar solvation energies in the interior of the channel and these are less than 5 kcal/mol above the solvation free energy for Na+ in water, in good agreement with experimental data on the activation barriers for ion permeation. It appears that the problems associated with previous calculations of energy profiles in membrane channels can be overcome by a consistent treatment of all the relevant electrostatic contributions. In particular, we find that the induced dipoles of the membrane and the protein contributes with approximately 10 kcal/mol to the solvation energy inside the channel and can therefore not be discarded in a realistic description of ion solvation in the Gramicidin channel.

Gramicidin↗
PubMed1989

Enzymes work by solvation substitution rather than by desolvation.

Considerable attention has recently been drawn to the hypothesis that enzymes catalyze their reactions by displacing solvent and creating an environment similar to the gas phase for the reacting substrates. This "desolvation hypothesis" is reexamined in this paper by defining a common reference energy for reactions in various environments. It is argued that consistent attempts to describe the actual energetics of enzymatic reactions, taking either gas phase or solution as a reference, would contradict the above hypothesis. That is, the enzyme does remove water molecules from its substrate, but substitutes these molecules for another polar environment (namely, its active site). By taking amide hydrolysis as an example, we use experimentally estimated solvation energies and analyze the reaction profile in the gas phase, in solution, and in enzyme active sites. We show that the gas-phase reaction is characterized by an enormous activation barrier (associated with forming the charged nucleophile from neutral fragments), although the nucleophilic attack is essentially barrierless. On the other hand, the enzyme and solution reactions are found to have similar reaction profiles, with a lower activation barrier for the enzymatic reaction. Presumably, the fact that previous analyses of this problem did not involve the construction of the relevant thermodynamic cycles (and quantitative estimates of the corresponding solvation energies) led to the desolvation hypothesis. Our conclusion is that enzyme active sites provide specific polar environments that do not resemble the gas phase but that are designed for electrostatic stabilization of ionic transition states and that "solvate" these states more than water does.

Binding Sites↗
PubMed1987

Aspects of model building applied to the C-terminal domain of the L12 protein from chloroplast ribosomes: a molecular dynamics study.

A 170 picosecond molecular dynamics trajectory has been calculated starting from a model-built structure of chloroplast CTF. Local conformational changes occur during the equilibration period. Thereafter, a dynamically stable structure is attained. The conformational changes involve a turn connecting two structural subdomains which has an amino acid insertion and several substitutions with respect to the E. coli sequence. Potential energy minimisation alone fails to detect such a change. The overall folding and atomic positional fluctuations are very similar to those found in MD simulations of the E. coli molecule. The combined use of computer graphics based model building and MD calculations has lead to a thermally stable putative structure for the chloroplast CTF.

Chemical Phenomena↗
PubMed1986

Molecular dynamics simulations of the holo and apo forms of retinol binding protein. Structural and dynamical changes induced by retinol removal.

The effects of removing retinol from the X-ray structure of holo-retinol binding protein are studied using the molecular dynamics technique. Structural and dynamical properties emerging from an 80 ps simulation of the apo form, for which no crystallographic structure is available, are compared with the results of a 70 ps trajectory of the holo-protein. Dynamical stationarity is attained after roughly 30 ps, and the resulting average structure is proposed as a reasonable model of the apo-protein. Conformational changes are observed for the loops at the beta-barrel entrance during the non-equilibrium part of the apo-trajectory. Tryptophan labelling experiments and retinoid reconstitution experiments point towards this part of the molecule as being involved in prealbumin binding. Structural changes in this region may therefore explain the differences in prealbumin affinity between the apo and holo forms. Furthermore, a change in the position of the alpha-helix, corresponding to a pivot around its C terminus, is observed for the apo-protein. The resulting conformation of the alpha-helix is found to be similar to that in apo-beta-lactoglobulin, which also can bind retinol and for which a crystal structure exists. The results from the holo simulation are compared to the crystallographic data and show good agreement. The dynamics of the secondary and tertiary structural elements are analysed and compared for the two forms. The beta-barrel is found to be extremely cooperative in its atomic motions in both simulations, and the top and bottom beta-sheets perform collective fluctuations with respect to each other in the low-frequency limit of the simulations. The dynamics of the alpha-helical region presents clear differences between the two forms; while the holo-protein has a well-defined spectrum for the longitudinal stretching mode, the apo form displays a fairly large bending of the alpha-helix at several points of the trajectory.

Computer Simulation↗
PubMed1986

Structural changes in retinol binding protein induced by retinol removal. A molecular dynamics study.

Relationships between structure and function for retinol binding protein (RBP) are elucidated with help of a 2.0 A resolution X-ray structure of the holo-protein and an average molecular dynamics (MD) structure of the apo-form. Comparisons between MD simulations of both the apo- and holo-forms with the X-ray holo-structure show conformational changes in apo-RBP that may be functionally significant. The average three dimensional structure obtained for apo-RBP is compared to the related protein apo-beta-lactoglobulin. Available biochemical information is consistent with structure/function relationships derived here.

Humans↗
PubMed1985

A molecular dynamics study of the C-terminal fragment of the L7/L12 ribosomal protein. Secondary structure motion in a 150 picosecond trajectory.

A 150 picosecond molecular dynamics computer simulation of the C-terminal fragment of the L7/L12 ribosomal protein from Escherichia coli is reported. The molecular dynamics results are compared with the available high-resolution X-ray data in terms of atomic positions, distances and positional fluctuations. Good agreement is found between the molecular dynamics results and the X-ray data. The form and parameters of the interaction potential energy function and the procedures for deriving it are discussed. Some current misunderstandings concerning the ways of evaluating the efficiency of molecular dynamics algorithms and of application of bond-length constraints in protein simulations are cleared up. The 150 picosecond trajectory has been scanned in a search for correlated motions within and between secondary structure elements. The beta-strands have diffusional stretching modes, and uncorrelated transversal displacements. The dynamic analysis of alpha-helices shows a variety of features. The atomic fluctuations differ between the helix ends; this effect reflects long time-scale motions. Two alpha-helices, alpha A and alpha C, show diffusive longitudinal stretching modes. The third helix, alpha B, has a correlated asymmetric longitudinal stretching; the N-terminal part dominates this behaviour. Furthermore, alpha B presents a librational motion with respect to the other parts of the molecule with a frequency of approximately 5 cm-1. This motion is coupled to helix stretching. Interestingly, the regions of highly conserved residues contain the most mobile parts of the molecule.

Bacterial Proteins↗
PubMed1984

The three-dimensional structure of retinol-binding protein.

The complex of retinol with its carrier protein, retinol-binding protein (RBP) has been crystallized and its three-dimensional structure determined using X-ray crystallography. Its most striking feature is an eight-stranded up-and-down beta barrel core that completely encapsulates the retinol molecule. The retinol molecule lies along the axis of the barrel with the beta-ionone ring innermost and the tip of the isoprene tail close to the surface.

Animals↗
PubMedDate not supplied

Q: a molecular dynamics program for free energy calculations and empirical valence bond simulations in biomolecular systems.

A new molecular dynamics program for free energy calculations in biomolecular systems is presented. It is principally designed for free energy perturbation simulations, empirical valence bond calculations, and binding affinity estimation by linear interaction energy methods. Evaluation of ligand-binding selectivity and free energy profiles for nucleophile activation in two protein tyrosine phosphatases as well as absolute binding affinity estimation for a lysine-binding protein are given as examples.

Algorithms↗