Ioannis N. Demetropoulos

Merlin-3.0 A multidimensional optimization environment

We present an optimization environment for multidimensional continuous functions. Robust and powerful algorithms are used that guarantee its effectiveness. The environment offers programmability and ease of use by providing a specialized operating system and a control language that can be used to create successful optimization strategies. We report on several applications where this software has been successfully used.

The Merlin control language for strategic optimization

Abstract Mcl is the programming language of the Merlin optimization environment. It can be used for the implementation of efficient optimization strategies, abolishing to a great extend the need for user intervention. The language is simple to learn and its structure is similar to Fortran. We report on successful applications where Mcl played an instrumental role, as for example in molecular physics problems and in the training of neural networks.

Molecular Dynamics as a pattern recognition tool: An automated process detects peptides that preserve the 3D arrangement of Trypsin's Active Site

Recently, the synthesis of a molecule has been reported that belongs to a Lysine based, branched cyclic peptide class. This work explores the ability of such molecules to preserve the 3D geometry of the Trypsins Active Site (TAS) by applying an integrated framework of automated computer procedures. The following four factors a) D/L chirality, b) different amino acids at different positions of the molecular scaffolds cyclic part, c) the application of AMBER and CHARMM force fields and d) different implicit solvation models were evaluated against TAS similarity. It was found that a number of molecules exhibit satisfactory geometric affinity to the TAS during extended Molecular Dynamics runs. We estimated that more than 2000 molecules (belonging to this class) could retain good similarity to the TAS arrangement.

Synthesis and reactions of 1-aryl-2-nitropyrroles. Structural and conformational study of ethyl N-[2′-[1′-(2-nitropyrrolyl)]phenyl]-N-toluene-4-sulfonamide glycinate

Nitration of 1-aryl(or 1-benzyl)pyrroles 1, 2 and 7 has provided the corresponding 2- and 3-nitropyrroles 3 and 5, 4 and 6, and 8 and 9 in a 1:2 ratio. Reductive cyclisation of 3 and 8, gave pyrrolo[1,2-a]quinazolines 11 and 12, and pyrrolo[1,2-b][2.4]benzodiazepine 13, respectively. A conformational study of 5 in the solid and liquid state using X-ray diffraction analysis, molecular dynamics calculations and NMR spectroscopy, is described.

How many conformers of the 1, 2, 3-propanetriol triacetate are present in gas phase and in aqueous solution?

Abstract We found 109 rotamers within 3 kcal from the global minimum of the triglyceride in vacuo and only 6 water-solvated rotamers within this range. Hydration restricts triacetins conformational flexibility which is an unusual situation for small polar molecules. The lowest solvated conformation forms a system of three ring-like formations as the three carbonyl oxygens approach the hydrogen of the mid carbon of the glyceride skeleton. The structures of the global minima were subjected to geometry optimization with ab initio methods in order to validate the results.

Ab initio molecular orbital calculations of solvent clusters of trans-N-methylacetamide: structure, ring cluster formation and out-of-plane deformation

The solvation of trans amides has been investigated by the use of full gradient optimization ab initio quantum mechanical calculation techniques. The complexes have been determined at the Hartree–Fock (HF) level with a 4-31G*/4-31G** basis set and at the second-order Moller–Plesset perturbation (MP2) level. Three NMA–water clusters were investigated: trans-NMA with two molecules of water forming a ring cluster at the amide oxygen; trans-NMA with two molecules of water at the amide oxygen forming hydrogen bonds along the direction of the lone-pair electrons; trans-NMA with one molecule of water at the CO group and one at the NH group. In addition, 4-31G* basis set calculations for trans-NMA with two molecules of acetonitrile were performed. The CO⋯H(W) hydrogen bond lengths, electron-density population analysis and molecular-orbital analysis of trans-NMA with two molecules of water at the amide oxygen demonstrate the importance of concurrent water–water and water–(carbonyl) oxygen hydrogen-bond interactions. The complex of trans-NMA with two molecules of water forming a ring cluster at the amide oxygen indicates the formation of a non-planar amide bond and the generation of a chiral centre at the amide nitrogen; this structure has a 5 % Boltzmann distribution at room temperature at the MP2 level. Vibrational-frequency analysis shows that its hydrogen-bonded water molecules are vibrationally coupled. Orbital analysis suggests that there is a considerable solute-occupied space reorganization caused by the rearrangement of the water solvent molecules. Comparisons are made with previous theoretical studies of amide–water interactions and experimental spectroscopic, X-ray and neutron-diffraction data on the hydration of amides, peptides and proteins.

Design, synthesis and catalytic activity of a serine protease synthetic model

The design, synthesis and catalytic properties of a cyclic branched peptide carrier that possesses the catalytic triad residues of the serine proteases is reported. The synthesis of the peptide model was totally completed on solid support using three different orthogonal amino protecting groups. Hydrolytic activity measurements against Suc-Ala-Ala-Ala-pNA substrate showed that it is hydrolysed by the peptide model to a small extent. Despite this small hydrolytic activity, it is the first time, to our knowledge, that hydrolysis of such a substrate is reported by an enzyme model compound. Contrary, this enzyme model peptide showed considerable activity against the Boc-Ala-pNP substrate (k cat =0.414 min−1 andK m =0.228 mm). These results suggest that the designed carrier brings in appropriate contact the catalytic triad residues (Ser, His, Asp) resulting in the obtained hydrolytic activity.

A supermolecule study of the effect of hydration on the conformational behaviour of leucine-enkephalin

SummaryA theoretical conformational study was performed on leu-enkephalin in its zwitterionic form, both in vacuo and in the presence of a number, n, of up to 13 water molecules saturating its first hydration shell. The intramolecular energy of enkephalin as well as the intermolecular enkephalin-water and water-water interaction energies were computed with the SIBFA procedure (Sum of Interactions Between Fragments Ab initio computed), which uses additive ab initio multipole systematics and analytical formulas grounded on ab initio SCF computations. Energy minimizations were performed with a polyvalent minimizer, Merlin, with which three distinct derivative and three distinct nonderivative minimizers can be activated in a sequential fashion.Eight different candidate conformations of enkephalin were used as starting points. These conformations are either those found in distinct X-ray structures, or those proposed on the basis of theoretical computations by other authors. In the absence of hydration, they converged towards distinct folded energy-minima, the best four ones being separated by an energy gap of 8.7 kcal/mol. In marked contrast, with up to n=13, the energetical separation between the six best conformers narrowed down to ≃ 4 kcal/mol. They can be characterized by: (a) either a direct or a water-mediated ammonium-carboxylate interaction; b) either a close proximity (as in morphine) or a large separation between the aromatic rings of Tyr and Phe (intercenter separations of ≃4.5 Å and ≃ 10.5 Å, respectively), with each of the four mutual combinations of (a) and (b) being represented.

LysinebasedTrypsinActSite(LysTAS): A configurational tool of the TINKER software to evaluate Lysine based branched cyclic peptides as potential chymotrypsin-mimetics

Serine proteases are members of a large class of proteolytic enzymes found in many organisms that have an important role in many biochemical processes, such as protein catabolism, digestion, blood pressure regulation, etc. Recently a Lysine based branched cyclic peptide synthesis has been reported; the peptide’s choice was assisted by computer aided molecular design [1]. LysinebasedTrypsinActSite(LysTAS) is a new tool that automated the above mentioned processes; it works as an extension of the wellknown software TINKER (http://dasher.wustl.edu/tinker/) [2]. The package builds peptidomimetic molecules that satisfy a particular design (figure 1) and grades them against chymotrypsin’s active site’s topology. At this stage we omitted the modelization of the binding site despite its obvious significance in catalysis. Our intention is to construct a leader compound with serine protease-like activity without further specificity. The concept behind this is Menger spatiotemporal hypothesis and the most recent “NAC” [3]. According to this approximation the ability of an enzyme to bind to the substrate (formation of the Michaelis complex (MC)) [4] by acquiring an approximate conformation is the most crucial step towards catalysis.

Static and frequency dependent polarizabilities and hyperpolarizabilities of H2Sn

The structure–polarization relationship was investigated in a series of polysulfanes, H2Sn. The reported results demonstrate that the forms of change of the polarizability components, αii, and the second hyperpolarizability components, γiiii, as well as the average values α and γ, respectively, of H2Sn with n are similar. This shows that polarizability components can be easily used to determine corresponding hyperpolarizability data. A remarkable change of the hyperpolarizabilities with the molecular geometry of H2Sn was found. This result can be used for the design of nonlinear optical materials with optimum properties. The present study uses the flexible σ bonded H2Sn and is complementary to the works that considered the effect of conformational changes of π‐conjugated systems on their hyperpolarizabities. The present computations were performed using the semiempirical approaches MNDO and MNDO/d, as well as ab initio methods with STO‐3G, extended with polarization and diffuse functions, and [3s2p/7s5p2d] sets for H2Sn. At the ab initio level, the electronic and the vibrational contributions to polarizabilities and hyperpolarizabilities were both computed for several members of H2Sn. The frequency dependence of the above contributions and the static limit were discussed. Electron correlation was taken into account for several test cases using MP2 theory. The selected methods and the variety of the approximations on which they rely allow the systematic consideration of the effect of changes of the geometry of H2Sn on their polarizabilities and second hyperpolarizabilities. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 1698–1715, 1998