Monte Carlo Energy Minimization Research Articles

Conformational search of antisense nucleotides

A preliminary MMFF implementation of selenium atom parameters necessary to model the nucleoside 1 is reported. X-ray structures of two compounds 1 and 2 have been used as references. Ab initio methods have been adopted for checking torsional energy profile and charge distribution. Monte Carlo calculations and energy minimization in solvation complete the conformational search.

Combined Monte Carlo-energy minimization analysis of Al-Fe disorder in Ca 2 FeAlO 5 brownmillerite

Combined Monte Carlo-energy minimization analysis of Al-Fe disorder in Ca 2 FeAlO 5 brownmillerite

The third-dimensional structure of the complex between an Fv antibody fragment and an analogue of the main immunogenic region of the acetylcholine receptor: A combined two-dimensional NMR, homology, and molecular modeling approach

Binding of autoantibodies to the acetylcholine receptor (AChR) plays a major role in the autoimmune disease Myasthenia gravis (MG). In this paper, we propose a structure model of a putative immunocomplex that gives rise to the reduction of functional AChR molecules during the course of MG. The model complex consists of the [G(70), Nle(76)] decapeptide analogue of the main immunogenic region (MIR), representing the major antigenic epitope of AChR, and the single chain Fv fragment of monoclonal antibody 198, a potent MG autoantibody. The structure of the complexed decapeptide antigen [G(70), Nle(76)]MIR was determined using two-dimensional nmr, whereas the antibody structure was derived by means of homology modeling. The final complex was constructed using calculational docking and molecular dynamics. We termed this approach "directed modeling," since the known peptide structure directs the prestructured antibody binding site to its final conformation. The independently derived structures of the peptide antigen and antibody binding site already showed a high degree of surface complementarity after the initial docking calculation, during which the peptide was conformationally restrained. The docking routine was a soft algorithm, applying a combination of Monte Carlo simulation and energy minimization. The observed shape complementarity in the docking process suggested that the structure assessments already led to anti-idiotypic conformations of peptide antigen and antibody fragment. Refinement of the complex by dynamic simulation yielded improved surface adaptation by small rearrangements within antibody and antigen. The complex presented herein was analyzed in terms of antibody-antigen interactions, properties of contacting surfaces, and segmental mobility. The structural requirements for AChR complexation by autoantibodies were explored and compared with experimental data from alanine scans of the MIR peptides. The analysis revealed that the N-terminal loop of the peptide structure, which is indispensable for antibody recognition, aligns three hydrophobic groups in a favorable arrangement leading to the burial of 40% of the peptide surface in the binding cleft upon complexation. These data should be valuable in the rational design of an Fv mutant with much improved affinity for the MIR and AChR to be used in therapeutic approaches in MG.

Prodock: Software package for protein modeling and docking

A new software package, Prodock, for protein modeling and flexible docking is presented. The protein system is described in internal coordinates with an arbitrary level of flexiblity for the proteins or ligands. The protein is represented by an all-atom model with the Ecepp/3 or Amber IV force field, depending on whether the ligand is a peptidic molecule or not. Prodock is based on a new residue data dictionary that makes the programming easier and the definition of molecular flexibility more straigthforward. Two versions of the dictionary have been constructed for the Ecepp/3 and Amber IV geometry, respectively. The global optimization of the energy function is carried out with the scaled collective variable Monte Carlo method plus energy minimization. The incorporation of a local minimization during the conformational sampling has been shown to be very important for distinguishing low-energy nonnative conformations from native structures. To make the Monte Carlo minimization method efficient for docking, a new grid-based energy evaluation technique using Bezier splines has been incorporated. This article includes some techniques and simulation tools that significantly improve the efficiency of flexible docking simulations, in particular forward/backward polypeptide chain generation. A comparative study to illustrate the advantage of using quaternions over Euler angles for the rigid-body rotational variables is presented in this paper. Several applications of the program Prodock are also discussed. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 412–427, 1999

Efficient dynamics in the space of contact maps

Two problems are of major importance in protein fold prediction: how to generate plausible conformations, and how to choose an energy function to identify the native state. Contact maps are a simple representation of protein structure and offer a promising framework to address these two issues. In this work we develop Monte Carlo dynamics in contact map space. The procedure is divided into four steps: non-local dynamics, in which large-scale "cluster" moves are performed (clusters are in approximate correspondence with secondary structure elements); local dynamics, in which secondary structure location is optimized; reconstruction, in which the physicality of the contact map is restored; and refinement, which consists of a further Monte Carlo energy minimization in real space. We demonstrate that such a dynamical procedure is effective in producing uncorrelated low-energy states. The procedure introduced in this paper very effectively generates a representative ensemble of conformations. We are able to show that existing sets of pairwise contact energy parameters are not suitable to single out the native state within this ensemble. The remaining outstanding issue in protein folding is to find an energy function that can discriminate the native state from decoys.

Interaction of calcium channel antagonists with calcium: spectroscopic and modeling studies on diltiazem and its Ca2+ complex.

Using spectral techniques, the solution conformation of diltiazem was studied in acetonitrile with special reference to the effect of Ca2+ on the drug structure. Complete assignment of the proton resonances in the 1H-NMR spectrum of the drug was made using one-and two-dimensional spectral analyses. A two-dimensional 1H-NOESY spectrum (in the phase-sensitive mode) was obtained to identify the interproton connectivities in the drug molecule. A molecular modeling program involving Monte Carlo simulation and energy minimization was employed to arrive at the structure of the drug. The program was run with and without the input of the interproton distances derived from the NOESY cross peaks. Both the protocols led to a structure of the drug which was generally similar to that reported from X-ray diffraction data on crystalline diltiazem hydrochloride (Kojic-Prodic, et al. Helv. Chim. Acta 1984, 67, 916-926). However, significant differences between the two structures were seen in the orientations of the substituent groups attached to the benzothiazepine ring. Substantial changes in the circular dichroic (CD) and 1H-NMR spectra of diltiazem were observed on addition of Ca2+ up to a mole ratio of 0.5 Ca2+ per drug. Relatively large changes were seen in 1H resonances of the N-methyl protons and the methylene protons attached to the heterocyclic nitrogen. Analysis of the binding isotherms from CD data at 22 +/- 1 degrees C indicated a 2:1 drug:Ca2+ "sandwich" complex with an estimated dissociation constant of 140 microM. One-dimensional difference NOE and two-dimensional NOESY spectra revealed interproton connectivities between two drug molecules that were compatible with the sandwich complex formation. The interproton distances derived from the volume integrals of the NOESY cross peaks were used as geometrical constraints in modeling the Ca(2+)-bound conformation of diltiazem. The minimum-energy conformation corresponded to the sandwich complex where Ca2+ was coordinated to three oxygens in each of the two drug molecules. Combined with our earlier data on the ability of diltiazem to translocate Ca2+ across the lipid bilayer in synthetic liposomes (Ananthanarayanan, V.S.; Taylor, L.; Pirritano, S.Biochem. Cell Biol. 1992, 70, 608-612), the structural data presented here point to a role for Ca2+ in the interaction of diltiazem with its membrane-bound receptor.

Atomistic simulation of void nucleation in aluminium lines

Abstract The formation of voids in aluminium interconnects in integrated circuits was studied atomistically with emphasis on nucleation. Input computational cells included different levels of concentrations of vacancies and stresses together with the typically observed structural defects (grain boundaries and dislocations) in metal lines. The input cells were relaxed using Monte Carlo (atom transpose) and static energy minimization (strain relaxation) techniques concurrently. Besides agglomeration of vacancies in unstrained crystals, the formation of vacancies in crystals under tension was found to be a main contributor to void nucleation. Climb and glide of dislocations were observed atomistically during the formation of voids. Compressive stresses in the metal lines, on the other hand, prevented the formation of voids.

Energy-optimized structure of antifreeze protein and its binding mechanism

A combination of Monte Carlo simulated annealing and energy minimization was utilized to determine the conformation of the antifreeze protein from the fish winter flounder. It was found from the energy-optimized structure that the hydroxyl groups of its four threonine residues, i.e. Thr2, Thr13, Thr24, Thr35, are aligned on almost the same line parallel to the helix axis and separated successively by 16·1, 16·0 and 16·2 Å, respectively, very close to the 16·6 Å repeat spacing along [011̄2] in ice. Based on such a space match, a zipper-like model is proposed to elucidate the binding mechanism of the antifreeze protein to ice crystals. According to the current model, the antifreeze protein may bind to an ice nucleation structure in a zipper-like fashion through hydrogen bonding of the hydroxyl groups of these four Thr residues to the oxygen atoms along the [011̄2] direction in ice lattice, subsequently stopping or retarding the growth of ice pyramidal planes so as to depress the freeze point. The calculated results and the binding mechanism thus derived accord with recent experimental observations. The mechanistic implications derived from such a special antifreeze molecule might be generally applied to elucidate the structure-function relationship of other antifreeze proteins with the following two common features: (1) recurrence of a Thr residue (or any other polar amino acid residue whose side-chain can form a hydrogen bond with water) in an 11-amino-acid period along the sequence concerned; and (2) a high percentage of Ala residue component therein. Further experiments are suggested to test the ice binding model.

Monte Carlo Study of Reconstruction of the Au (110) Surface Using Equivalent Crystal Theory

AbstractThe (110) surface of gold is known experimentally to undergo a 1 × 2 reconstruction which is believed to be of the “missing row” type. There have been a number of theoretical studies of the energetics and geometry of this reconstruction. In this work, we present new results obtained using two versions of the Equivalent Crystal Theory (ECT). The ECT has proven to be quite accurate in providing predictions of surface energies and planar relaxations. The extended version of the ECT has been modified to better describe such quantities as elastic constants and shear energies. We have computed the energetics and geometry of the missing-row reconstructed surface, in both unrelaxed and relaxed form, using a Monte Carlo energy minimization technique, allowing relaxation of the positions of atoms up to three layers deep. We compare these results with previous theoretical work and with available experimental data.

On the multiple-minima problem in the conformational analysis of polypeptides. II. An electrostatically driven Monte Carlo method--tests on poly(L-alanine).

AbstractA new approach to the multiple‐minima problem in protein folding is presented. It is assumed that the molecule is driven toward the native structure by three types of mechanism. The first one involves an optimization of the electrostatic interactions, whereby the molecule evolves toward conformations in which the charge distribution becomes energetically more favorable. The second mechanism involves a Monte Carlo–energy minimization approach, and the third one is a backtrack mechanism that acts in the opposite direction, increasing the energy—the third type of movement provides a means to perturb the molecule when it is trapped in a stable but energetically unfavorable local energy minimum. This paper describes the implementation of a model based on these mechanisms, and illustrates its effectiveness by computations on different arbitrary starting conformations of a terminally blocked 19‐residue chain of poly(L‐alanine) for which the global minimum apparently corresponds to the right‐handed α‐helix. In all cases, the global minimum was attained, even when the starting conformation was a left‐handed α‐helix. In the latter case, the trajectory of conformations passed through partially melted forms of the left‐handed α‐helix (because of electrostatic defects at the ends), and then through the formation of structures leading to the more stable right‐handed α‐helix.