István Kolossváry

Superspreading driven by Marangoni flow

The spontaneous spreading (called superspreading) of aqueous trisiloxane ethoxylate surfactant solutions on hydrophobic solid surfaces is a fascinating phenomenon with several practical applications. For example, the ability of trisiloxane ethoxylate surfactants to enhance the spreading of spray solutions on waxy weed leaf surfaces, such as velvetleaf (Abutilion theophrasti), makes them excellent wetting agents for herbicide applications. The superspreading ability of silicone surfactants has been known for decades, but its mechanism is still not well understood. In this paper, we suggest that the spreading of trisiloxane ethoxylates is controlled by a surface tension gradient, which forms when a drop of surfactant solution is placed on a solid surface. The proposed model suggests that, as the spreading front stretches, the surface tension increases (the surfactant concentration becomes lower) at the front relative to the top of the droplet, thereby establishing a dynamic surface tension gradient. The driving force for spreading is due to the Marangoni effect, and our experiments showed that the higher the gradient, the faster the spreading. A simple model describing the phenomenon of superspreading is presented. We also suggest that the superspreading behavior of trisiloxane ethoxylates is a consequence of the molecular configuration at the air/water surface (i.e. small and compact hydrophobic part), as shown by molecular dynamics modeling. We also found that the aggregates and vesicles formed in trisiloxane solutions do not initiate the spreading process and therefore these structures are not a requirement for the superspreading process.

LOW-MODE CONFORMATIONAL SEARCH ELUCIDATED : APPLICATION TO C39H80 AND FLEXIBLE DOCKING OF 9-DEAZAGUANINE INHIBITORS INTO PNP

We previously described a new conformational search method, termed low‐mode search (LMOD), and discussed its utility for conformational searches performed on cycloalkanes and a cyclic penta‐peptide. 1 In this report, we discuss a rigorous implementation of mode following (c‐LMOD) for conformational searching, and we demonstrate that for a conformational search involving cycloheptadecane, this rigorous implementation is capable of finding all of the previously known structures. To the best of our knowledge, this is the first computational proof that mode following can be used for conformational searches conducted on a complex molecular system. We show, however, that, as expected, it is generally inefficient to perform a conformational search in this manner. Nonetheless, c‐LMOD has been shown to be an excellent method for conducting conformational analyses involving conformational interconversions, where the location of saddle points is important. We also describe refinement to our original LMOD procedure (l‐LMOD) and discuss its utility for a difficult conformational search problem, namely locating the global minimum energy conformation of C39H80. For this search, l‐LMOD combined with limited torsional Monte Carlo movement was able to locate the lowest energy structures yet reported, and significantly outperformed a pure torsional Monte Carlo and a genetic algorithm‐based search. Furthermore, we also demonstrate the utility of l‐LMOD combined with random translation/rotation of a ligand for the extremely difficult problem of docking flexible ligands into flexible protein binding sites on a system that includes 9‐deaza‐guanine‐based inhibitors docked into the flexible biding site of PNP. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 1671–1684, 1999

Hessian‐free low‐mode conformational search for large‐scale protein loop optimization: application to c‐jun N‐terminal kinase JNK3

A Hessian‐free low‐mode search algorithm has been developed for large‐scale conformational searching. The new method is termed LLMOD, and it utilizes the ARPACK package to compute low‐mode eigenvectors of a Hessian matrix that is only referenced implicitly, through its product with a series of vectors. The Hessian × vector product is calculated utilizing a finite difference formula based on gradients. LLMOD is the first conformational search method that can be applied to fully flexible, unconstrained protein structures for complex loop optimization problems. LLMOD has been tested on a particularly difficult model system, c‐jun N‐terminal kinase JNK3. We demonstrate that LLMOD was able to correct a P38/ERK2/HCL‐based homology model that grossly misplaced the crucial glycine‐rich loop in the ATP‐binding site.

Torsional flexing: conformational searching of cyclic molecules in biased internal coordinate space

A new stochastic (Monte Carlo) procedure, termed torsional flexing, has been devised for searching the conformational space of cyclic molecules. Torsional flexing causes a local, torsion angle‐biased, distortion of a ring bond in a cyclic molecule. Because torsional flexing does not cause large atomic movements, even when it is applied to several bonds simultaneously, subsequent energy minimization generally proceeds rapidly. Nevertheless, the torsional flexing method is prone to generate structures that cross energy barriers so that the structure resulting after energy minimization is frequently a different conformer of the cyclic molecule. Conformational searches on cycloheptadecane, oxobrefeldin A, cyclopenta‐L‐alanine, and rifamycin SV based upon torsional flexing indicated that torsional flexing is among the best methods yet devised for searching the conformational space of flexible cyclic molecules.

Application of the frozen atom approximation to the GB/SA continuum model for solvation free energy

The generalized Born/surface area (GB/SA) continuum model for solvation free energy is a fast and accurate alternative to using discrete water molecules in molecular simulations of solvated systems. However, computational studies of large solvated molecular systems such as enzyme–ligand complexes can still be computationally expensive even with continuum solvation methods simply because of the large number of atoms in the solute molecules. Because in such systems often only a relatively small portion of the system such as the ligand binding site is under study, it becomes less attractive to calculate energies and derivatives for all atoms in the system. To curtail computation while still maintaining high energetic accuracy, atoms distant from the site of interest are often frozen; that is, their coordinates are made invariant. Such frozen atoms do not require energetic and derivative updates during the course of a simulation. Herein we describe methodology and results for applying the frozen atom approach to both the generalized Born (GB) and the solvent accessible surface area (SASA) parts of the GB/SA continuum model for solvation free energy. For strictly pairwise energetic terms, such as the Coulombic and van‐der‐Waals energies, contributions from pairs of frozen atoms can be ignored. This leaves energetic differences unaffected for conformations that vary only in the positions of nonfrozen atoms. Due to the nonlocal nature of the GB analytical form, however, excluding such pairs from a GB calculation leads to unacceptable inaccuracies. To apply a frozen‐atom scheme to GB calculations, a buffer region within the frozen‐atom zone is generated based on a user‐definable cutoff distance from the nonfrozen atoms. Certain pairwise interactions between frozen atoms in the buffer region are retained in the GB computation. This allows high accuracy in conformational GB comparisons to be maintained while achieving significant savings in computational time compared to the full (nonfrozen) calculation. A similar approach for using a buffer region of frozen atoms is taken for the SASA calculation. The SASA calculation is local in nature, and thus exact SASA energies are maintained. With a buffer region of 8 Å for the frozen‐atom cases, excellent agreement in differences in energies for three different conformations of cytochrome P450 with a bound camphor ligand are obtained with respect to the nonfrozen cases. For various minimization protocols, simulations run 2 to 10.5 times faster and memory usage is reduced by a factor of 1.5 to 5. Application of the frozen atom method for GB/SA calculations thus can render computationally tractable biologically and medically important simulations such as those used to study ligand–receptor binding conformations and energies in a solvated environment.

Theoretical study of intramolecular hydrogen bonding and molecular geometry of 2-trifluoromethylphenol

The conformational behavior of 2‐trifluoromethylphenol was investigated by means of theoretical calculations. Four characteristic structures have been found on the potential energy hypersurface of the compound: anti form (local minimum), in which the hydroxy hydrogen points away from the trifluoromethyl group; and three syn forms (the hydrogen points towards the trifluoromethyl group), with different trifluoromethyl torsions (global minimum, one low and another one high lying saddle‐point). The geometry of these conformers were optimized by ab initio calculations using 6‐31G** basis set. The effects of electron correlation were investigated by MP2 and various DFT methods. To investigate the intramolecular interaction in the syn forms, the electron density distribution was calculated at the MP2 level of theory. In the structure corresponding to the global minimum at the MP2/6‐31G** level a bond critical point was found in Baders sense between the hydroxy hydrogen and a fluorine of the trifluoromethyl group indicating hydrogen bonding interaction. The length of the hydrogen bond, 1.98 Å, corresponds to medium strength interaction. The O(SINGLE BOND)H bond is slightly twisted and the C(SINGLE BOND)F bond, interacting with it, is considerably twisted out of the plane of the benzene ring to the same side of the ring. The most pronounced geometrical consequence of the hydrogen bond is the 0.02‐Å lengthening of the C(SINGLE BOND)F bond participating in its formation. All the other geometrical changes in 2‐trifluoromethylphenol, as compared with trifluoromethylbenzene and phenol, are also consistent with the phenomenon of resonance‐assisted hydrogen bonding.

The conformational space of selected aldo-pyrano-hexoses

Abstract The conformational space of selected aldo-pyrano-hexoses was searched by the MM2 ∗ -SUMM (systematic unbounded multiple minimum) molecular mechanics conformational search technique. The first 19 structures of lowest energy were analyzed at the HF/ 3-21G, 6-31G(d) and generalized gradient approximation-density functional (GGA-DFT) levels of theory. The interactions of the hydroxyl groups were analyzed by employing the gradient vector field theory.

Compare-Conformer: a program for the rapid comparison of molecular conformers based on interatomic distances and torsion angles.

A computer program for comparison of the conformations of a number of related molecular structures is described. The comparisons are performed on either interatomic distances or torsion angles. The comparisons are accomplished on ordered pairs of distances or torsion angles, and the distance comparisons can be performed in a manner that allows permutation of the distance pairs being compared. The algorithm utilizes bit-string Boolean operations that allow the comparisons to be performed rapidly. The program should be useful for computer-assisted molecular modeling studies in which the viable conformers of bioactive analogues are compared in order to locate those conformers that place key substituents in the same spatial orientation.

On the degeneracy of the Hessian matrix

A widespread notion in the computational chemistry literature about the Hessian matrix has been revisited, namely, that the Hessian matrix over Cartesian space is sixfold degenerate due to the three translational and three rotational degrees of freedom. It has been shown that this is true only at critical points on the potential energy hypersurface, otherwise the Hessian matrix is only threefold degenerate. The rotational degrees of freedom generally do not cause degeneracy in the Hessian matrix away from critical points.

On searching the conformational space of cyclic molecules. Conformational interconversion pathways in trans-cyclosilkenes

Abstract By employing the SUMM procedure of J.M. Goodman and W.C. Still (J. Comput. Chem., 12 (1991) 1110) and methodology previously developed in our laboratories (e.g. FLEX for conformational searching of cyclic molecules and XTST for location of saddle point structures) we have been able to locate the transition state structure on the MM3 potential energy hypersurface corresponding to jump rope rotation of trans -cyclononene. We were unable to locate the transition state for trans -cyclooctene on either the MM2 or MM3 potential energy surface, probably due to an overestimation of the repulsive interactions in this highly crowded structure.