In silico analysis of metal coordination geometry in arsenic,beryllium, and lead bound structures

Metal toxicity is a potential hazard to health and toxic effects of metals have been implicated in many diseases. Understanding the interaction of toxic metals becomes vital to prevent hazards following its association in living systems. Coordination chemistry helps in predicting the metal environments like coordinating residues, coordination space, metal coordination geometry, etc. Our work aimed at predicting the coordination of toxic metals arsenic, lead, and beryllium. In this work, we analyzed coordination for each metal from a set of arsenic, beryllium and lead bound structures which were retrieved from the Protein Data Bank. The structures were validated using B-factor and occupancy of the coordinating residues towards the metals. Coordination patterns such as chelate residues, chelate length, geometry, coordination number and structural architecture were predicted. Coordination geometry of the metals was exposed beyond the coordination space with their coordination number ranging from 2 to 11. Analysis of metal environment revealed the acidic amino acids aspartic acid, glutamic acid, and the basic amino acids lysine, histidine, and cysteine to be predominant in coordinating with the metals. Chelate patterns like DDVMITAK, DWNVTVK, ESGKNSS for beryllium, CCCSK, DSDWD for lead and FLICVI and LKHHKEE for arsenic were predicted to be common through extended coordination space. The distinct molecular geometries such as pentagonal bipyramid and square planar were observed only in lead bound structures but not in beryllium and arsenic bound structures. Beryllium had a larger influence than arsenic and lead, based on conformational changes owing to the presence of the metals. Our coordination study puts forth several propositions based on the metal environment that would help in designing chelation strategies.     

Determination of the structure of fusaproliferin by1H-NMR and distance geometry

The absolute configuration of fusaproliferin, a toxic metabolite produced byFusarium proliferation, was determined by the combined use of¹H NMR and distance geometry. The configuration of double bonds has been determined in agreement with NOESY buildup data. An R configuration for C10 was determined using Mosher's method. Processing the constraints obtained from NOESY experiments with a distance geometry program, a limited number (80) of possible structures was derived. An agglomerative nonhierarchical method of clustering was used in order to place these structures into classes suggested by the data, and not previously defined in any way. This statistical method showed that indeed the structures could be grouped in four classes. One of these classes is represented by a single structure, with the highest sum of violations and was discarded. All other structures have the same chirality; respectively S for C14 and R for C15. In solution the overall conformation is quite well defined in the region of the five-member ring and the planes of double bonds C2–C3 and C11–C12, while near to C8 and C9 internal flexibility appears evident.     

Reaction of apple pectin modified by pharmacophores,with copper(II) cations

The reaction of apple pectin modified by organic pharmacophores (nicotinic, salicylic, 5-aminosalicylic, and anthranilic acids) with Cu(II) cations was studied by spectral methods. The compositions of the complexes were determined and their stability constants, as well as the thermodynamic parameters (ΔH ⁰, ΔG ⁰, ΔS ⁰) of the complex formation were calculated. The structure of the drug in the polymeric ligand was found to affect certain physicochemical properties of the metal complexes.     

Comparison of knowledge-based and distance geometry approaches for generation of molecular conformations.

A knowledge-based approach for generating conformations of molecules has been developed. The method described here provides a good sampling of the molecule's conformational space by restricting the generated conformations to those consistent with the reference database. The present approach, internally named et for enumerate torsions, differs from previous database-mining approaches by employing a library of much larger substructures while treating open chains, rings, and combinations of chains and rings in the same manner. In addition to knowledge in the form of observed torsion angles, some knowledge from the medicinal chemist is captured in the form of which substructures are identified. The knowledge-based approach is compared to Blaney et al.'s distance geometry (DG) algorithm for sampling the conformational space of molecules. The structures of 113 protein-bound molecules, determined by X-ray crystallography, were used to compare the methods. The present knowledge-based approach (i) generates conformations closer to the experimentally determined conformation, (ii) generates them sooner, and (iii) is significantly faster than the DG method.     

GEOM: A new tool for molecular modelling based on distance geometry calculations with NMR data

Summary GEOM is a new graphics tool which allows the use of distance geometry to compute linear and cyclic structures typically arising in drug design situations. Modified amino acids or monomeric organic entities can be easily constructed in an interactive way and deposited in the library of the distance geometry program together with geometric information required for structure calculation in dihedral angle space. In addition, GEOM is able to produce all files needed to calculate a structure based on NMR data (NOE and J-coupling constraints) and it permits the graphic analysis and comparison of computed structures. The application of GEOM is demonstrated in three examples: modelling of cyclosporin A structures with and without a limited set of H-bond constraints and modelling of a cyclic hexapeptide with a full NMR data set.     

The oxidation of diamond: the geometry and stretching frequency of carbonyl on the (100) surface

Microwave plasma deposited (100) diamond films have been thermally oxidized in dry O2 between 500 and 723 degrees C. The roughness of a single crystalline grain following oxidation is consistent with a layer-by-layer mechanism for the removal of carbon monoxide. The resulting surface exhibits infrared absorption bands at 1731 and 905 cm-1, attributed to the stretching and bending modes of a surface bonded carbonyl group. The former is within 1 cm-1 of the structurally analogous molecule 2-adamantanone. These data are consistent with the carbonyl groups being present on diamond (100) terraces.     

Applications of weighting and chirality strategies for distance geometry algorithms to an enterotoxin peptide analog

Significant improvements are made to a recent algorithm that finds molecular conformations using distance geometry on nuclear magnetic resonance data. Weighting factors for the nearest approximation of the distance matrix to a data matrix are allowed to vary between iterations of the algorithm. These changes are proportional to the error of the distance between atoms in the configuration and the nuclear magnetic resonance data bounds. The weight changes increase the rate of convergence by an order of magnitude. Penalty functions are proposed to ensure the correct chirality. Numerical results for these modifications and subsequent energy calculations using CHARMm are given for an analog of the heat stable (ST) enterotoxin peptide STh produced byE. coli in humans.     

Long flexible polymers interacting with ellipsoids, cylinders, and needles

The depletion interactions of ellipsoidal colloidal particles in a solution of long polymer chains are analyzed. Of primary concern are the limiting cases in which the ellipsoid reduces to a cylinder of infinite length and finite radius and a "needle" of finite length and vanishing radius. Relations are obtained between the polymer effects induced by a needle that is much shorter than the polymer size and by a cylinder with radius much smaller than the polymer size. These imply exact quantitative results for the orientation-dependent depletion interaction between a short needle and a wall. Qualitative differences between the needle and thin disk are discussed.     

The geometry and intermolecular stretching force constant of the dimer of carbonyl sulphide and hydrogen cyanide as determined by rotational spectroscopy

The ground-state rotational spectra of four isotopic species of the carbonyl sulphide—hydrogen cyanide dimer have been observed and measured by using pulsed-nozzle, Fourier-transform microwave spectroscopy. The spectroscopic constants B₀, D_J and χ(¹⁴N) have been determined as follows.      

12.

Lightweight,flexible, nanorod electrode with high electrocatalytic activity     

《Electrochemistry communications》2013

We report on a dropcasting method to fabricate lightweight and mechanically flexible electrodes from gold nanorods. The nanorod electrodes possess extremely high electroactive areas, which lead to greatly enhanced electrocatalysis towards oxygen reduction reaction and methanol oxidation reaction when compared to conventional gold disk electrodes.     

13.

Exercises in molecular gymnastics--bending, stretching and twisting porphyrins     

Senge MO 《Chemical communications (Cambridge, England)》2006,(3):243-256

The functional versatility of tetrapyrroles as natural cofactors is related to their conformational flexibility where manipulation of the macrocycle conformation allows a fine-tuning of their physicochemical properties. This feature article gives a personal account of the synthesis and solid state structural characterization of highly substituted, non-planar porphyrins. Their conformational analysis identifies sterically strained tetrapyrroles as a versatile class of biomimetic compounds with tailor-made properties.     

14.

Evaluation of several two-step scoring functions based on linear interaction energy, effective ligand size, and empirical pair potentials for prediction of protein-ligand binding geometry and free energy     

Rahaman O  Estrada TP  Doren DJ  Taufer M  Brooks CL  Armen RS 《Journal of chemical information and modeling》2011,51(9):2047-2065

The performances of several two-step scoring approaches for molecular docking were assessed for their ability to predict binding geometries and free energies. Two new scoring functions designed for "step 2 discrimination" were proposed and compared to our CHARMM implementation of the linear interaction energy (LIE) approach using the Generalized-Born with Molecular Volume (GBMV) implicit solvation model. A scoring function S1 was proposed by considering only "interacting" ligand atoms as the "effective size" of the ligand and extended to an empirical regression-based pair potential S2. The S1 and S2 scoring schemes were trained and 5-fold cross-validated on a diverse set of 259 protein-ligand complexes from the Ligand Protein Database (LPDB). The regression-based parameters for S1 and S2 also demonstrated reasonable transferability in the CSARdock 2010 benchmark using a new data set (NRC HiQ) of diverse protein-ligand complexes. The ability of the scoring functions to accurately predict ligand geometry was evaluated by calculating the discriminative power (DP) of the scoring functions to identify native poses. The parameters for the LIE scoring function with the optimal discriminative power (DP) for geometry (step 1 discrimination) were found to be very similar to the best-fit parameters for binding free energy over a large number of protein-ligand complexes (step 2 discrimination). Reasonable performance of the scoring functions in enrichment of active compounds in four different protein target classes established that the parameters for S1 and S2 provided reasonable accuracy and transferability. Additional analysis was performed to definitively separate scoring function performance from molecular weight effects. This analysis included the prediction of ligand binding efficiencies for a subset of the CSARdock NRC HiQ data set where the number of ligand heavy atoms ranged from 17 to 35. This range of ligand heavy atoms is where improved accuracy of predicted ligand efficiencies is most relevant to real-world drug design efforts.     

15.

Interaction of spermine,spermidine, and putrescine with heparin bound to sepharose beads     

B. Tadolini  L. Cabrini 《Applied biochemistry and biotechnology》1984,9(2):143-152

The binding of the polyamines spermine and spermidine, and of their precursor, putrescine, to heparin-sepharose have been investigated to provide the basic data for further application of this resin in the study of polyamine biological function.

1. Spermine binds heparin-sepharose in a cooperative phase, the empirical index of cooperativity is two, and the apparent binding constant is 1.41 × 10⁶ M^-1.
2. Spermidine binds heparin-sepharose in a cooperative and strong noncooperative phase. In the cooperative phase, the index of cooperativity is two and the apparent binding constant is 1.56 × 10⁶ M^-. In the strong noncooperative phase, the apparent binding constant is 2 × 10⁵ M^-1.
3. Putrescine binds heparin-sepharose in a strong noncooperative and a weak noncooperative phase. In the strong noncooperative phase the apparent binding constant is 2.6 × 10⁵ M^-1. In the weak noncooperative phase, the apparent binding constant is 3.2 × 10³ M^-1.

     

16.

Studies on organotin compounds using the Del Re method III. Variations in tin-chlorine,tin-carbon and tin-hydrogen stretching frequencies and tin-chlorine bond distance in organotin compounds     

R. GuptaB. Majee 《Journal of organometallic chemistry》1972

The concept of bond order has been extended to Del Re calculations, and the bond orders of tin-chlorine and tin-carbon bonds in Me_4-nSnCl_n (n = 1 to 4) type compounds have been calculated. The tin-chlorine bond order increases progressively from 0.922 in Me₃SnCl to 0.977 in SnCl₄, and correlates satisfactorily with the experimental tin-chlorine bond distances. The tin-carbon bond order, on the other hand, remains almost constant, in agreement with the constancy of tin-carbon bond distance in the series. The average tin-chlorine, tin-carbon and tin-hydrogen stretching frequencies in similar compounds vary linearly with the calculated bond polarities indicating variation in bond polarity to be the dominating factor. The unusually low values of the tin-carbon stretching frequency for the tin-vinyl bond compared to the tin-methyl bond in Me₃ViSn and Et₂Vi₂Sn can also be explained in terms of larger polarity of the tin-vinyl bond in these compounds.     

17.

Increasing structure dimensionality of copper(I) complexes by varying the flexible thioether ligand geometry and counteranions     

Peng R  Li D  Wu T  Zhou XP  Ng SW 《Inorganic chemistry》2006,45(10):4035-4046

This work focuses on the systematic investigation of the influences of pyrimidine-based thioether ligand geometries and counteranions on the overall molecular architectures. A N-containing heterocyclic dithioether ligand 2,6-bis(2-pyrimidinesulfanylmethyl)pyridine (L1) and three structurally related isomeric bis(2-pyrimidinesulfanylmethyl)benzene (L2-L4) ligands have been prepared. On the basis of the self-assembly of CuX (X = I, Br, Cl, SCN, or CN) and the four structurally related flexible dithioether ligands, we have synthesized and characterized 10 new metal-organic entities, Cu4(L1)2I4 1, Cu4(L1)2Br4 2, [Cu2(L2)2I2.CH3CN]n 3, [Cu(L3)I]n 4, [Cu(L3)Br]n 5, [Cu(L3)CN]n 6, [Cu(L4)CN]n 7, [Cu2(L4)I2]n 8, [Cu2(L4)(SCN)2]n 9, and [[Cu6I5(L4)3](BF4).H2O]n 10, by elemental analyses, IR spectroscopy, and X-ray crystallography. Single-crystal X-ray analyses show that the 10 Cu(I) complexes possess an increasing dimensionality from 0D (1 and 2) to 1D (3-5) to 2D (6-9) to 3D (10), which indicates that the ligand geometry takes an essential role in the framework formation of the Cu(I) complexes. The influence of counteranions and pi-pi weak interactions on the formation and dimensionality of these coordination polymers has also been explored. In addition, the photoluminescence properties of Cu(I) coordination polymers 4-10 in the solid state have been studied.     

18.

Binding of acetylcholine and tetramethylammonium to flexible cyclophane receptors: improving on binding ability by optimizing host's geometry     

Sarri P  Venturi F  Cuda F  Roelens S 《The Journal of organic chemistry》2004,69(11):3654-3661

The structure of a cyclophanic tetraester (1), previously employed for investigations on the cation-pi interaction, has been optimized to better accommodate acetylcholine (ACh) and tetramethylammonium (TMA) guests. Following indications from molecular modeling calculations, a flexible cyclophane receptor of significantly improved binding properties has been obtained by removing the four carbonyl groups of the parent host. 2,11,20,29-Tetraoxa[3.3.3.3]paracyclophane (2) was prepared by an improved procedure, which was conveniently devised to avoid the formation of contiguous cyclooligomers that caused serious separation issues. Association of 2 with TMA picrate was measured in CDCl(3) at T = 296 K by (1)H NMR titrations and compared to binding data obtained for a set of reference hosts, including the parent tetraester 1, the corresponding cyclophanic tetraamine, the open-chain counterpart of 2, and its cyclooligomers from pentamer to octamer. Binding enhancements ranging from 15-fold (with respect to the tetraester and the tetraamine) to over 80-fold (with respect to the open-chain tetraether) were achieved by geometry optimization of the host. Binding of 2 to ACh and TMA was investigated for a variety of counterions. A constant binding free energy increment of nearly 8 kJ mol(-1) with respect to 1 was observed, independent from the anion and irrespective of the different structure of the cationic guests. Results showed that the electrostatic inhibiting contribution of the counterion to the cation's binding is a characteristic constant of each anion. The value of -Delta G degrees = 44.9 kJ mol(-1) extrapolated for TMA in the absence of a counterion indicates that 28-34 kJ mol(-1) of binding free energy are lost in ion pairing.     

19.

GROMACS: fast, flexible, and free   总被引：37，自引：0，他引：37  

Van Der Spoel D  Lindahl E  Hess B  Groenhof G  Mark AE  Berendsen HJ 《Journal of computational chemistry》2005,26(16):1701-1718

This article describes the software suite GROMACS (Groningen MAchine for Chemical Simulation) that was developed at the University of Groningen, The Netherlands, in the early 1990s. The software, written in ANSI C, originates from a parallel hardware project, and is well suited for parallelization on processor clusters. By careful optimization of neighbor searching and of inner loop performance, GROMACS is a very fast program for molecular dynamics simulation. It does not have a force field of its own, but is compatible with GROMOS, OPLS, AMBER, and ENCAD force fields. In addition, it can handle polarizable shell models and flexible constraints. The program is versatile, as force routines can be added by the user, tabulated functions can be specified, and analyses can be easily customized. Nonequilibrium dynamics and free energy determinations are incorporated. Interfaces with popular quantum-chemical packages (MOPAC, GAMES-UK, GAUSSIAN) are provided to perform mixed MM/QM simulations. The package includes about 100 utility and analysis programs. GROMACS is in the public domain and distributed (with source code and documentation) under the GNU General Public License. It is maintained by a group of developers from the Universities of Groningen, Uppsala, and Stockholm, and the Max Planck Institute for Polymer Research in Mainz. Its Web site is http://www.gromacs.org.     

20.

Cooperativity, partially bound states, and enthalpy-entropy compensation     

Hunter CA  Tomas S 《Chemistry & biology》2003,10(11):1023-1032

Efforts to develop a quantitative understanding of molecular recognition rely on the additivity of individual intermolecular interactions, and cooperativity represents one of the major potential stumbling blocks. A chemical double-mutant cycle has been used to experimentally measure cooperativity between functional group interactions within a complex framework. The interaction between two aromatic groups varies by 0.2 +/- 0.4 kJ mol(-1) in synthetic H-bonded complexes that differ by 8-13 kJ mol(-1) in overall stability. In these systems, the free energies associated with individual intermolecular interactions can therefore be reliably treated in an additive fashion. The results suggest that alternative explanations should be considered for cooperative phenomena observed in other systems, and a rationale based on the population of partially bound states in flexible molecules is proposed to account for the enthalpic chelate effect and enthalpy-entropy compensation.     

Lightweight,flexible, nanorod electrode with high electrocatalytic activity

We report on a dropcasting method to fabricate lightweight and mechanically flexible electrodes from gold nanorods. The nanorod electrodes possess extremely high electroactive areas, which lead to greatly enhanced electrocatalysis towards oxygen reduction reaction and methanol oxidation reaction when compared to conventional gold disk electrodes.     

Exercises in molecular gymnastics--bending, stretching and twisting porphyrins

The functional versatility of tetrapyrroles as natural cofactors is related to their conformational flexibility where manipulation of the macrocycle conformation allows a fine-tuning of their physicochemical properties. This feature article gives a personal account of the synthesis and solid state structural characterization of highly substituted, non-planar porphyrins. Their conformational analysis identifies sterically strained tetrapyrroles as a versatile class of biomimetic compounds with tailor-made properties.     

Evaluation of several two-step scoring functions based on linear interaction energy, effective ligand size, and empirical pair potentials for prediction of protein-ligand binding geometry and free energy

The performances of several two-step scoring approaches for molecular docking were assessed for their ability to predict binding geometries and free energies. Two new scoring functions designed for "step 2 discrimination" were proposed and compared to our CHARMM implementation of the linear interaction energy (LIE) approach using the Generalized-Born with Molecular Volume (GBMV) implicit solvation model. A scoring function S1 was proposed by considering only "interacting" ligand atoms as the "effective size" of the ligand and extended to an empirical regression-based pair potential S2. The S1 and S2 scoring schemes were trained and 5-fold cross-validated on a diverse set of 259 protein-ligand complexes from the Ligand Protein Database (LPDB). The regression-based parameters for S1 and S2 also demonstrated reasonable transferability in the CSARdock 2010 benchmark using a new data set (NRC HiQ) of diverse protein-ligand complexes. The ability of the scoring functions to accurately predict ligand geometry was evaluated by calculating the discriminative power (DP) of the scoring functions to identify native poses. The parameters for the LIE scoring function with the optimal discriminative power (DP) for geometry (step 1 discrimination) were found to be very similar to the best-fit parameters for binding free energy over a large number of protein-ligand complexes (step 2 discrimination). Reasonable performance of the scoring functions in enrichment of active compounds in four different protein target classes established that the parameters for S1 and S2 provided reasonable accuracy and transferability. Additional analysis was performed to definitively separate scoring function performance from molecular weight effects. This analysis included the prediction of ligand binding efficiencies for a subset of the CSARdock NRC HiQ data set where the number of ligand heavy atoms ranged from 17 to 35. This range of ligand heavy atoms is where improved accuracy of predicted ligand efficiencies is most relevant to real-world drug design efforts.     

Interaction of spermine,spermidine, and putrescine with heparin bound to sepharose beads

The binding of the polyamines spermine and spermidine, and of their precursor, putrescine, to heparin-sepharose have been investigated to provide the basic data for further application of this resin in the study of polyamine biological function.

1. Spermine binds heparin-sepharose in a cooperative phase, the empirical index of cooperativity is two, and the apparent binding constant is 1.41 × 10⁶ M^-1.
2. Spermidine binds heparin-sepharose in a cooperative and strong noncooperative phase. In the cooperative phase, the index of cooperativity is two and the apparent binding constant is 1.56 × 10⁶ M^-. In the strong noncooperative phase, the apparent binding constant is 2 × 10⁵ M^-1.
3. Putrescine binds heparin-sepharose in a strong noncooperative and a weak noncooperative phase. In the strong noncooperative phase the apparent binding constant is 2.6 × 10⁵ M^-1. In the weak noncooperative phase, the apparent binding constant is 3.2 × 10³ M^-1.

     

Studies on organotin compounds using the Del Re method III. Variations in tin-chlorine,tin-carbon and tin-hydrogen stretching frequencies and tin-chlorine bond distance in organotin compounds

The concept of bond order has been extended to Del Re calculations, and the bond orders of tin-chlorine and tin-carbon bonds in Me_4-nSnCl_n (n = 1 to 4) type compounds have been calculated. The tin-chlorine bond order increases progressively from 0.922 in Me₃SnCl to 0.977 in SnCl₄, and correlates satisfactorily with the experimental tin-chlorine bond distances. The tin-carbon bond order, on the other hand, remains almost constant, in agreement with the constancy of tin-carbon bond distance in the series. The average tin-chlorine, tin-carbon and tin-hydrogen stretching frequencies in similar compounds vary linearly with the calculated bond polarities indicating variation in bond polarity to be the dominating factor. The unusually low values of the tin-carbon stretching frequency for the tin-vinyl bond compared to the tin-methyl bond in Me₃ViSn and Et₂Vi₂Sn can also be explained in terms of larger polarity of the tin-vinyl bond in these compounds.     

Increasing structure dimensionality of copper(I) complexes by varying the flexible thioether ligand geometry and counteranions

This work focuses on the systematic investigation of the influences of pyrimidine-based thioether ligand geometries and counteranions on the overall molecular architectures. A N-containing heterocyclic dithioether ligand 2,6-bis(2-pyrimidinesulfanylmethyl)pyridine (L1) and three structurally related isomeric bis(2-pyrimidinesulfanylmethyl)benzene (L2-L4) ligands have been prepared. On the basis of the self-assembly of CuX (X = I, Br, Cl, SCN, or CN) and the four structurally related flexible dithioether ligands, we have synthesized and characterized 10 new metal-organic entities, Cu4(L1)2I4 1, Cu4(L1)2Br4 2, [Cu2(L2)2I2.CH3CN]n 3, [Cu(L3)I]n 4, [Cu(L3)Br]n 5, [Cu(L3)CN]n 6, [Cu(L4)CN]n 7, [Cu2(L4)I2]n 8, [Cu2(L4)(SCN)2]n 9, and [[Cu6I5(L4)3](BF4).H2O]n 10, by elemental analyses, IR spectroscopy, and X-ray crystallography. Single-crystal X-ray analyses show that the 10 Cu(I) complexes possess an increasing dimensionality from 0D (1 and 2) to 1D (3-5) to 2D (6-9) to 3D (10), which indicates that the ligand geometry takes an essential role in the framework formation of the Cu(I) complexes. The influence of counteranions and pi-pi weak interactions on the formation and dimensionality of these coordination polymers has also been explored. In addition, the photoluminescence properties of Cu(I) coordination polymers 4-10 in the solid state have been studied.     

Binding of acetylcholine and tetramethylammonium to flexible cyclophane receptors: improving on binding ability by optimizing host's geometry

The structure of a cyclophanic tetraester (1), previously employed for investigations on the cation-pi interaction, has been optimized to better accommodate acetylcholine (ACh) and tetramethylammonium (TMA) guests. Following indications from molecular modeling calculations, a flexible cyclophane receptor of significantly improved binding properties has been obtained by removing the four carbonyl groups of the parent host. 2,11,20,29-Tetraoxa[3.3.3.3]paracyclophane (2) was prepared by an improved procedure, which was conveniently devised to avoid the formation of contiguous cyclooligomers that caused serious separation issues. Association of 2 with TMA picrate was measured in CDCl(3) at T = 296 K by (1)H NMR titrations and compared to binding data obtained for a set of reference hosts, including the parent tetraester 1, the corresponding cyclophanic tetraamine, the open-chain counterpart of 2, and its cyclooligomers from pentamer to octamer. Binding enhancements ranging from 15-fold (with respect to the tetraester and the tetraamine) to over 80-fold (with respect to the open-chain tetraether) were achieved by geometry optimization of the host. Binding of 2 to ACh and TMA was investigated for a variety of counterions. A constant binding free energy increment of nearly 8 kJ mol(-1) with respect to 1 was observed, independent from the anion and irrespective of the different structure of the cationic guests. Results showed that the electrostatic inhibiting contribution of the counterion to the cation's binding is a characteristic constant of each anion. The value of -Delta G degrees = 44.9 kJ mol(-1) extrapolated for TMA in the absence of a counterion indicates that 28-34 kJ mol(-1) of binding free energy are lost in ion pairing.     

GROMACS: fast, flexible, and free

This article describes the software suite GROMACS (Groningen MAchine for Chemical Simulation) that was developed at the University of Groningen, The Netherlands, in the early 1990s. The software, written in ANSI C, originates from a parallel hardware project, and is well suited for parallelization on processor clusters. By careful optimization of neighbor searching and of inner loop performance, GROMACS is a very fast program for molecular dynamics simulation. It does not have a force field of its own, but is compatible with GROMOS, OPLS, AMBER, and ENCAD force fields. In addition, it can handle polarizable shell models and flexible constraints. The program is versatile, as force routines can be added by the user, tabulated functions can be specified, and analyses can be easily customized. Nonequilibrium dynamics and free energy determinations are incorporated. Interfaces with popular quantum-chemical packages (MOPAC, GAMES-UK, GAUSSIAN) are provided to perform mixed MM/QM simulations. The package includes about 100 utility and analysis programs. GROMACS is in the public domain and distributed (with source code and documentation) under the GNU General Public License. It is maintained by a group of developers from the Universities of Groningen, Uppsala, and Stockholm, and the Max Planck Institute for Polymer Research in Mainz. Its Web site is http://www.gromacs.org.     

Cooperativity, partially bound states, and enthalpy-entropy compensation

Efforts to develop a quantitative understanding of molecular recognition rely on the additivity of individual intermolecular interactions, and cooperativity represents one of the major potential stumbling blocks. A chemical double-mutant cycle has been used to experimentally measure cooperativity between functional group interactions within a complex framework. The interaction between two aromatic groups varies by 0.2 +/- 0.4 kJ mol(-1) in synthetic H-bonded complexes that differ by 8-13 kJ mol(-1) in overall stability. In these systems, the free energies associated with individual intermolecular interactions can therefore be reliably treated in an additive fashion. The results suggest that alternative explanations should be considered for cooperative phenomena observed in other systems, and a rationale based on the population of partially bound states in flexible molecules is proposed to account for the enthalpic chelate effect and enthalpy-entropy compensation.