Full Atom Research Articles

Predicting peptide structures using NMR data and deterministic global optimization

The ability to analyze large molecular structures by NMR techniques requires efficient methods for structure calculation. Currently, there are several widely available methods for tackling these problems, which, in general, rely on the optimization of penalty-type target functions to satisfy the conformational restraints. Typically, these methods combine simulated annealing protocols with molecular dynamics and local minimization, either in distance or torsional angle space. In this work, both a novel formulation and algorithmic procedure for the solution of the NMR structure prediction problem is outlined. First, the unconstrained, penalty-type structure prediction problem is reformulated using nonlinear constraints, which can be individually enumerated for all, or subsets, of the distance restraints. In this way, the violation can be controlled as a constraint, in contrast to the usual penalty-type restraints. In addition, the customary simplified objective function is replaced by a full atom force field in the torsional angle space. This guarantees a better description of atomic interactions, which dictate the native structure of the molecule along with the distance restraints. The second novel portion of this work involves the solution method. Rather than pursue the typical simulated annealing procedure, this work relies on a deterministic method, which theoretically guarantees that the global solution can be located. This branch and bound technique, based on the αBB algorithm, has already been successfully applied to the identification of global minimum energy structures of peptides modeled by full atom force fields. Finally, the approach is applied to the Compstatin structure prediction, and it is found to possess some important merits when compared to existing techniques. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 1354–1370, 1999

Refinement of the crystal structure π-Al 9FeMg 3Si 5

The crystal structure of the quaternary so-called π-phase, which was originally solved from photographic single crystal data, has been refined from single crystal automatic four circle counter data. Single crystals were obtained from the residue of a slowly cooled melt of nominal composition (in at %) Al 74.1Fe 0.5Mg 8.4Si 17.0, which was dissolved in butanol. The composition of the π-phase crystal was Al 9Fe 1Mg 3.5Si 5.0. The π-phase crystallizes in a unique structure type (Al 9FeMg 3Si 5-type) with the noncentrosymmetric hexagonal space group P 6 ̄ 2m−D 3 3h , No. 189. The lattice parameters obtained from a Gandolfi camera were a=0.6625(2) nm and c=0.7910(4) nm, Z=1. For 366 reflections (‖F 0‖≥3 σ) the residual values are R=∑ (‖Δ F‖/∑‖ F 0‖)=0.064, R w=0.075. Whereas previous structure determinations claimed full atom order, the present refinement clearly indicates that the crystal structure is partially ordered with a random distribution of 0.94 Al+0.06 Mg in the 6i-sites. Furthermore, whilst lattice and atom parameter essentially correspond to the values derived earlier, the new composition as a result of the refinement (Al 8.7Fe 1Mg 3.3Si 5) is in close agreement with the experimental composition Al 9FeMg 3.5Si 5.

Protein folding simulations with genetic algorithms and a detailed molecular description

We have explored the application of genetic algorithms (GA) to the determination of protein structure from sequence, using a full atom representation. A free energy function with point charge electrostatics and an area based solvation model is used. The method is found to be superior to previously investigated Monte Carlo algorithms. For selected fragments, up to 14 residues long, the lowest free energy structures produced by the GA are similar in conformation to the corresponding experimental structures in most cases. There are three main conclusions from these results. First, the genetic algorithm is an effective method for searching amongst the compact conformations of a polypeptide chain. Second, the free energy function is generally able to select native-like conformations. However, some deficiencies are identified, and further development is proposed. Third, the selection of native-like conformations for some protein fragments establishes that in these cases the conformation observed in the full protein structure is largely context independent. The implications for the nature of protein folding pathways are discussed.

Ab initio structure prediction for small polypeptides and protein fragments using genetic algorithms.

Ab initio folding simulations have been performed on three peptides, using a genetic algorithm-based search method which operates on a full atom representation. Conformations are evaluated with an empirical force field parameterized by a potential of mean force analysis of experimental structures. The dominant terms in the force field are local and nonlocal main chain electrostatics and the hydrophobic effect. Two of the simulated structures were for fragments of complete proteins (eosinophil-derived neurotoxin (EDN) and the subtilisin propeptide) that were identified as being likely initiation sites for folding. The experimental structure of one of these (EDN) was subsequently found to be consistent with that prediction (using local hydrophobic burial as the determinant for independent folding). The simulations of the structures of these two peptides were only partly successful. The most successful folding simulation was that of a 22-residue peptide corresponding to the membrane binding domain of blood coagulation factor VIII (Membind). Three simulations were performed on this peptide and the lowest energy conformation was found to be the most similar to the experimental structure. The conformation of this peptide was determined with a C alpha rms deviation of 4.4 A. Although these simulations were partly successful there are still many unresolved problems, which we expect to be able to address in the next structure prediction experiment.

Modelling a nematic liquid crystal

Abstract The bulk phase liquid crystalline behaviour of a cyclic siloxane with a pentamethylcyclosiloxane core and biphenyl-4-allyloxybenzoate mesogens (BCS) was studied using molecular dynamics (MD) and wide angle X-ray analysis. This material exhibits partial crystallinity at room temperature and liquid crystalline behaviour above 120° C. For the MD simulations an ensemble of 27 molecules with 135 mesogenic units was simulated and a molecular mechanics force field was used to model the structural anisotropy of the siloxane molecules. Simulations were carried out both at room temperature and at an elevated temperature (425 K). Room temperature simulations showed that, contrary to our initial assumptions, the low energy molecular conformations were not cylindrical but splayed in shape. During the simulation a smectic-like, tilted layer structure was found to evolve for the cluster when full atom potentials were used, while no such development was observed when electrostatic interactions were neglected. The presence of a tilted layered structure was also suggested by the X-ray data. These results indicate that long range electrostatic interactions are significant for the molecular system under study. In order to calculate the orientational order parameter, the orientation of the molecular axis had to be determined. This was achieved by describing the mesogen shapes to be ellipsoidal and defining the principal axis of the ellipsoids to be the molecular directors. By sampling over 200 ps of simulation at 425 K, the time averaged order parameter (S) was calculated. The calculated S of 0.36 was comparable to the value of 0.4–0.45 found from the experimental data. Apart from providing insight into the relative importance of the various competing forces in the formation of the liquid crystalline phase, these simulations are also expected to be useful in predicting the mesophase behaviour of liquid crystalline systems.

Simulations of the folding pathway of triose phosphate isomerase-type alpha/beta barrel proteins.

Simulations of the folding pathways of two large alpha/beta proteins, the alpha subunit of tryptophan synthase and triose phosphate isomerase, are reported using the knight's walk lattice model of globular proteins and Monte Carlo dynamics. Starting from randomly generated unfolded states and with no assumptions regarding the nature of the folding intermediates, for the tryptophan synthase subunit these simulations predict, in agreement with experiment, the existence and location of a stable equilibrium intermediate comprised of six beta strands on the amino terminus of the molecule. For the case of triose phosphate isomerase, the simulations predict that both amino- and carboxyl-terminal intermediates should be observed. In a significant modification of previous lattice models, this model includes a full heavy atom side chain description and is capable of representing native conformations at the level of 2.5- to 3-A rms deviation for the C alpha positions, as compared to the crystal structure. With a well-balanced compromise between accuracy of the protein description and the computer requirements necessary to perform simulations spanning biologically significant amounts of time, the lattice model described here brings the possibility of studying important biological processes to present-day computers.

Lower bounds for the energy levels of the lithium atom

A recent modification of the intermediate hamiltonian method, intended to circumvent the problem associated with a low-lying continuum in the operator H 0, has been applied to the lithium atom with a basis of discrete hydrogenic functions. The intended raising of the continuum occurs, but not to the extent that the beginning of the continuum is raised above the ground state of the atom; indications are that no basis of discrete hydrogenic eigenfunctions can accomplish this. Since these calculations were performed on the full lithium atom hamiltonian, they are not strictly comparable to those of Fox and Siglillito, in which a simplified hamiltonian was used.