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Photosystem II (PSII) is a membrane-bound protein complex that oxidizes water to produce energized protons, which are used to built up a proton gradient across the thylakoidal membrane in the leafs of plants. This light-driven reaction is catalyzed by withdrawing electrons from the Mn4CaO5-cluster (Mn-cluster) in four discrete oxidation steps [S1−(S4/S0)] characterized in the Kok-cycle. In order to understand in detail the proton release events and the subsequent translocation of such energized protons, the protonation pattern of the Mn-cluster need to be elucidated. The new high-resolution PSII crystal structure from Umena, Kawakami, Shen, and Kamiya is an excellent basis to make progress in solving this problem. Following our previous work on oxidation and protonation states of the Mn-cluster, in this work, quantum chemical/electrostatic calculations were performed in order to estimate the pKa of different protons of relevant groups and atoms of the Mn-cluster such as W2, O4, O5 and His337. In broad agreement with previous experimental and theoretical work, our data suggest that W2 and His337 are likely to be in hydroxyl and neutral form, respectively, O5 and O4 to be unprotonated. This article is part of a Special Issue entitled: Photosynthesis Research for Sustainability: Keys to Produce Clean Energy.

Combination of an electron-rich molecule (e.g. chloride anion or nitrile group) with a chlorinated cyclohexasilane ring produces a supramolecular inverse sandwich complex formed by two guests (Cl(-) or RC≡N) strongly bonded to both faces of a planar host (Si6 ring). In-depth theoretical studies were carried out to investigate the nature of the bonding interactions that generate such a stable complex. Second-order Møller-Plesset perturbation theory (MP2) calculations confirmed that the presence of the Cl substituents is fundamental to the stability of the supramolecular assemblies. The density functional theory (DFT) functional wB97XD gave an estimation of the contribution of dispersion interactions to the binding energy. These interactions become more important as the Cl atoms of the rings are systematically replaced by methyl groups or hydrogen atoms. Analysis of the topology of the electron density and the reduced density gradient gave insight into the binding of the studied supramolecular assemblies.

Water plays a pivotal role in the correct functioning of proteins. Hydration is fundamental to their stability and flexibility, to folding process and specific functions, and to protein protein interactions. In this work, the effects of solvation on proteins dynamics have been investigated by employing molecular dynamics simulations and using myoglobin as a model system. The investigation has been focused on solvent waters residing around/inside the protein, with average times of up to tens of nanoseconds, revealing that these slow waters may have significant effects on biological functioning of the protein. Our study pointed out that water is able to interact with proteins in diverse ways, leading to different kinds of perturbations in their intrinsic dynamic behavior. In particular, for myoglobin it was found that a water molecule can (i) "block" entry/escape of ligands to/from a particular docking site, (ii) act as a "wedge" modulating the dynamics of internal cavities, or (iii) join a "flow" of waters taking a ligand into (or "washing" a ligand away from) the protein interior. The information gathered in this work allowed us to provide a fingerprint of protein solvation state, the hydration sites map, which may represent a novel tool for comparing different forms/species of globular proteins.

The binding of the ligand N,N′,N″,N″′-tetrakis{2,4-bis[(dipyridin-2-yl)amino]-1,3,5-triazin-2-yl}-1,4,8,11-tetraazacyclotetradecane (azadendtriz) to four copper(II) ions generates two electron-deficient cavities formed by four coordinated pyridine rings that are capable of hosting electron-rich guests. The molecular structures of [Cu4(azadendtriz)Cl4](Cl)4(H2O)13 (1) and [Cu4(azadendtriz)Br4](Br)4(H2O)28 (2), determined from single-crystal X-ray data, reveal that the π-acidic receptor binds a chloride anion through anion–π interactions in 1, whereas it hosts a water molecule through lone-pair–π interactions in 2. This differentiation between Br– and Cl– may be explained by the different size of the (hydrated) anions.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Mononuclear nickel(II) and copper(II) complexes, namely, (C6H9N2)2[Ni(ntaH)2] (1), (C5H7N2)2[Cu(mal)2(H2O)2] (2), and (C5H7N2)4[Ni(mal)2(H2O)2](NO3)2 (3) [ntaH3 = nitrilotriacetic acid; C6H8N2H = protonated 2-amino-4-picoline; malH2 = malonic acid; C5H7N2 = protonated 2-aminopyridine] have been synthesized in water and their crystal structures have been determined by single crystal X-ray diffraction. In all the complexes, robust bimolecular cyclic hydrogen bonding R22(8) motifs are observed between the protonated heteroaromatic N-rings and the metal-carboxylate complexes. Moreover, the aromatic molecules are engaged in carbonyl···π and anion···π interactions with the noncoordinated carbonyl moieties of the metal complexes and with a nitrate ion respectively, giving rise to remarkable carbonyl···π/π···π/carbonyl···π and carbonyl···π/π···π/π···anion interactions having sandwich type topologies. In 1 and 3, the carbonyl···π interactions are one of the weak forces responsible for the stabilization of the fina...

Density functional theory calculations have been employed to investigate the role of structural properties of copper phenanthroline complexes for DNA-cleavage activity. Structural changes imposed on the coordination geometries of Cu(phen)(2)(+,2+) (phen = 1,10-phenanthroline) linked by a serinol bridge (abbreviated as Clip) were studied, as well as their energetic profiles. Our calculations show that structures of these copper complexes (in this work named as clipped complexes) strongly depend on the position of the link, rather than on the copper oxidation state. Ionization energies slightly differ among the three selected complexes, while inner-sphere reorganization energies more markedly depend on the serinol link. However, the relative rates of the redox reaction of Cu(phen)(2), Cu(2-Clip-phen), and Cu(3-Clip-phen) were found not to correlate with their relative DNA-cleavage activity experimentally observed. Thus, the serinol link mainly affects the structural properties of copper phenanthroline complexes rather than their electronic properties. Docking simulations of clipped and nonclipped Cu(I) phenanthroline complexes on a DNA 16mer, d[CGCTCAACTGTGATAC](2), were finally performed to assess how different structural properties could affect the formation of DNA adducts. This analysis revealed that the most stable adducts of Cu(phen)(2)(+) and Cu(3-Clip-phen)(+) with DNA bind in the minor groove, whereas Cu(2-Clip-phen)(+) binds preferentially into the major groove.

Density functional calculations and Atoms in Molecules analysis are used to investigate the role of covalent and hydrogen bondings in determining the binding of transition metal complexes to guanine, and the subsequent effect on pairing with cytosine. Hydrogen bonding is ubiquitous, and typically contributes ca. 10% to overall binding, a value that varies with the coordination site on guanine, as well as metal and ligands. Early transition metals show a clear preference for the O6 position, while later ones prefer N7, the crossover point coming at the vanadium group. Metallation at N7 causes a redistribution of hydrogen bonding strength between guanine and cytosine, but does not greatly affect the overall pairing energy. In contrast, metallation at O6 strongly reduces the pairing energy, as may be expected given the role of O6 in pairing guanine with cytosine. This effect can be quantified using electron density properties, and seems to be due to both electrostatic repulsion from the positive metal centre and a redistribution of electron density within guanine itself. Qualitative agreement with experimental mass spectroscopic results is obtained.

The supramolecular bonding contacts driving the recognition of chloride ions by macrocyclic imidazolium-based receptors have been investigated by density functional theory calculations, both in vacuo and in solution (DMSO). This computational study reveals that the most stable host-guest complexes in vacuo and solution are different. While the anion interacts by means of two C-H···Cl(-) hydrogen bonds with the host molecule in vacuo (in a similar manner to that observed in the published single-crystal X-ray structure of the Cl-host complex), four C-H···Cl(-) contacts are clearly present in solution, as observed experimentally by earlier studies. In addition, the computed optimal Cl-host complex in solution confirms that the cavity of the host macrocycle, formed by four aromatic rings, does not includes the anions, which are located outside the cyclic receptor with which they interact through two CPh-H···Cl(-) hydrogen bonds and two unconventional (CIm-H)(+)···X(-) interactions.

Extensive quantum chemical DFT calculations were performed on the high-resolution (1.9 Å) crystal structure of photosystem II in order to determine the protonation pattern and the oxidation states of the oxygen-evolving Mn cluster. First, our data suggest that the experimental structure is not in the S(1)-state. Second, a rather complete set of possible protonation patterns is studied, resulting in very few alternative protonation patterns whose relevance is discussed. Finally, we show that the experimental structure is a mixture of states containing highly reduced forms, with the largest contribution (almost 60%) from the S(-3)-state, Mn(II,II,III,III).

The one-pot reaction of Mn(OAc)3 with two equivalents of 6-(pyridine-2-ylhydrazonomethyl)phenol (Hphp) in methanol leads to a unique leuco-verdazyl-type ring. The remarkable cyclodimerization reaction is proposed to involve a number of one-electron oxidative steps mediated by Mn3+ ions, as well as a very uncommon 1,2-radical aryl migration and a nucleophilic attack of the solvent, i.e. methanol., Support from the Graduate Research School Combination “Catalysis” and the COST program Action D35/0011 is acknowledged. Coordination of some of our research by the FP6 Network of Excellence “Magmanet” (contract number 515767) is also kindly acknowledged. The Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the US Department of Energy under Contract No. DE-AC02- 05CH11231. J. Tang thanks Changchun Institute of Applied Chemistry (Start-up) and National Natural Science Foundation of China (Grants 20871113 and 20921002) for their financial support.

Internal cavities, which are central to the biological functions of myoglobin, are exploited by gaseous ligands (e.g., O(2), NO, CO, etc.) to migrate inside the protein matrix. At present, it is not clear whether the ligand makes its own way inside the protein or instead the internal cavities are an intrinsic feature of myoglobin. To address this issue, standard molecular dynamics simulations were performed on horse-heart met-myoglobin with no ligand migrating inside the protein matrix. To reveal intrinsic internal pathways, the use of a statistical approach was applied to the cavity calculation, with special emphasis on the major pathway from the distal pocket to Xe1. Our study points out the remarkable dynamical behavior of Xe4, whose "breathing motions" may facilitate migration of ligands through the distal region. Additionally, our results highlight a two-way path for a ligand to diffuse through the proximal region, possibly allowing an alternative route in case Xe1 is occupied. Finally, our approach has led us to the identification of key residues, such as leucines, that may work as switches between cavities.

Two compounds, namely, [TTPH(2)](Cl)(2) x 4 H(2)O (1) and [TTPH(2)](Br)(2) x 4 H(2)O (2), (TTP = 4'-p-tolyl-2,2':6',2''-terpyridine) were synthesized from purely aqueous media and characterized by physical techniques. In the solid-state structures of these compounds, interesting supramolecular assemblies are observed. In 1, an unusual staircase-like architecture of the tape of edge-shared planar water hexamer is of importance, where the chloride ions are at the two edges of the tape. In 2, the polymeric nature of the water-bromide assembly is of interest, where discrete open-cube water octamers are doubly bridged by bromide ions. Semiempirical and DFT calculations confirm that the nature of the anion indeed affects the topology of the water-halide assemblies. We conclude that the protonated [TTPH(2)](2+) species can act as appropriate receptors for halide ions, which in turn act as a matrix for the formation of polymeric 1D water-halide assemblies.

A new hydrogen-bonded dinuclear copper(II) coordination compound has been synthesized from the Schiff-base ligand 6-(pyridine-2-ylhydrazonomethyl)phenol (Hphp). The molecular structure of [Cu(2)(php)(2)(H(2)O)(2)(ClO(4))](ClO(4))(H(2)O) (1), determined by single-crystal X-ray diffraction, reveals the presence of two copper(II) centers held together by means of two strong hydrogen bonds, with O...O contacts of only 2.60-2.68 A. Temperature-dependent magnetic susceptibility measurements down to 3 K show that the two metal ions are antiferromagnetically coupled (J = -19.8(2) cm(-1)). This exchange is most likely through two hydrogen-bonding pathways, where a coordinated water on the first Cu, donates a H bond to the O atoms of the coordinated php at the other Cu. This strong O...H(water) bonding interaction has been clearly evidenced by theoretical calculations. In the relatively few related cases from the literature, this exchange path, mediated by a (neutral) coordinated water molecule, was not recognized.

The solid-state structure of an alkaline-earth metal complex reveals the formation of a remarkable supramolecular framework based on concurrent lone pair-pi, pi-pi, and pi-anion interactions whose stability has been investigated by density functional theory.

Copper-1,10-phenanthroline (phen) complexes Cu(phen)(2)(), Cu(2-Clip-phen), and Cu(3-Clip-phen) (Clip = a serinol bridge between the phen parts) are typically employed as DNA-cleaving agents and are now becoming increasingly important for building multifunctional drugs with improved cytotoxic properties. For instance, Cu(3-Clip-phen) has been combined with distamycin-like minor-groove binders and cisplatin-derivatives, leading to promising results. Density Functional Theory (DFT) and docking calculations as well as molecular dynamics (MD) simulations were performed to describe the mode of binding to DNA of these complexes. Our data suggest the minor-groove binding to be more probable than (partial) intercalation and major-groove binding. In addition, it was found that a combination of factors including planarity, van der Waals interactions with DNA, and structural complementarities may be the key for the cleavage efficiency of these copper complexes.

The rational design of a ligand containing two electron-poor pi-rings, i.e. a triazine and a pentafluorophenoxy groups, has allowed the preparation of a copper complex where both the anticipated anion...pi interactions are present.

(ImH)[trans-RuCl(4)(DMSO-S)(Im)], (Im = imidazole, DMSO-S = S-bonded dimethylsulfoxide), NAMI-A, is the first anticancer ruthenium compound that successfully completed Phase I clinical trials. NAMI-A shows a remarkable activity against lung metastases of solid tumors, but is not effective in the reduction of primary cancer. The structurally similar (ImH)[trans-RuCl(4)(Im)(2)], ICR (or KP418), and its indazole analog (KP1019) are promising candidate drugs in the treatment of colorectal cancers, but have no antimetastatic activity. Despite the pharmacological relevance of these compounds, no rationale has been furnished to explain their markedly different activity. While the nature of the chemical species responsible for their antimetastatic/anticancer activity has not been determined, it has been suggested that the difference between reduction potentials of NAMI-A and ICR may be the key to the different biological responses they induce. In this work, Density Functional Theory calculations were performed to investigate the hydrolysis of NAMI-A and ICR in both Ru(III) and Ru(II) oxidation states, up to the third aquation. In line with experimental findings, our calculations provide a picture of the hydrolysis of NAMI-A and ICR mainly as a stepwise loss of chloride ligands. While dissociation of Im is unlikely under neutral conditions, that of DMSO becomes competitive with the loss of chloride ions as the hydrolysis proceeds. Redox properties of NAMI-A and ICR and of their most relevant hydrolytic intermediates were also studied in order to monitor the effects of biological reductants on the mechanism of action. Our findings may contribute to the identification of the active compounds that interact with biological targets, and to explain the different biological activity of NAMI-A and ICR.

Compounds mimicking the enzyme nitrogenase represent promising alternative routes to the current Haber-Bosch industrial synthesis of ammonia from molecular hydrogen and nitrogen. In this work, we investigated the full catalytic cycle of one of such compounds, Mo(HIPTN3N) (with HIPT = hexaisopropylterphenyl), by means of DFT calculations. Our results suggest these large ligands to exert mainly a steric influence on the structural properties of the catalyst. In addition, we provided a structural and electronic characterization of the putative reaction intermediates along with a picture of the electronic mechanism of molecular nitrogen N-N bond breaking. A large discrepancy was observed between calculated and experimental reaction free energies, suggesting that in the present case the predictability of DFT reaction energies is limited. Investigation of explicit solvation of specific catalytic intermediates as well as of the protonation and reducing agents reveal the crucial role played by the solvent molecules (benzene and heptane) particularly for protonation steps. Furthermore, the analysis of several DFT functionals indicates that these have to be carefully chosen in order to reproduce the energetic profile of reduction steps. This study shows how DFT calculations may be a powerful tool to describe structural and electronic properties of the intermediates of the catalytic cycle, yet, due to the complexity of the system, reaction energies cannot be easily reproduced without a careful choice of the solvation model and the exchange-correlation functional.

QM/MM calculations were employed to investigate the role of hy- drogen bonding and p stacking in sev- eral single- and double-stranded cispla- tin-DNA structures. Computed geo- metrical parameters reproduce experi- mental structures of cisplatin and its complex with guanine-phosphate-gua- nine. Following QM/MM optimisation, single-point DFT calculations allowed estimation of intermolecular forces through atoms in molecules (AIM) analysis. Binding energies of platinated single-strand DNA qualitatively agree with myriad experimental and theoreti- cal studies showing that complexes of guanine are stronger than those of ade- nine. The topology of all studied com- plexes confirms that platination strong- ly affects the stability of both single- and double-stranded DNAs: Pt! N! H···X (X = N or O) interactions are ubiquitous in these complexes and ac- count for over 70% of all H-bonding interactions. The p stacking is greatly reduced by both mono- and bifunction- al complexation: the former causes a loss of about 3-4 kcalmol ! 1 , whereas the latter leads to more drastic disrup- tion. The effect of platination on Watson-Crick GC is similar to that found in previous studies: major redis- tribution of energy occurs, but the overall stability is barely affected. The BH&H/AMBER/AIM approach was also used to study platination of a double-stranded DNA octamer d(CCTG*G*TCC)·dA for which an experimental structure is available. Comparison between theory and experiment is satisfactory, and also reproduces previous DFT-based studies of analogous structures. The effect of platination is similar to that seen in model systems, although the effect on GC pairing was more pronounced. These calculations also reveal weaker, secondary interactions of the form Pt···O and Pt···N, detected in several single- and double-stranded DNA.

QM/MM calculations have been employed to investigate the role of hydrogen bonding and pi-stacking in single- and double-stranded DNA oligonucleotides. DFT calculations and Atoms in Molecules analysis on QM/MM-optimized structures allow characterization and estimation of the energies of pi-stacking and hydrogen-bond interactions. This shows that pi-stacking interactions depend on the number and the nature of the DNA bases for single-stranded nucleotides; for instance, guanines are found to be involved in strong hydrogen bonds, whereas adenines interact mainly via stacking interactions. The role of interbase hydrogen bonding was explored: the -NH2 groups of guanine, adenine, and cytosine participate in N-H...O and N-H...N interactions. These are much stronger in single-strand oligonucleotides, where the -NH2 groups are highly nonplanar. In double-stranded DNA, the strong base-pairing hydrogen bonds of complementary bases lead to more planar -NH2 groups, which tend to be involved in pi-stacking interactions rather than H-bonds. The use of AIM also allows us to evaluate the interplay of pi-stacking and H-bonding, suggesting that cooperativity does occur, but is generally limited to about 1-2 kcal/mol.

The suitability of a hybrid density functional to qualitatively reproduce geometric and energetic details of parallel pi-stacked aromatic complexes is presented. The hybrid functional includes an ad hoc mixture of half the exact (HF) exchange with half of the uniform electron gas exchange, plus Lee, Yang, and Parr's expression for correlation energy. This functional, in combination with polarized, diffuse basis sets, gives a binding energy for the parallel-displaced benzene dimer in good agreement with the best available high-level calculations reported in the literature, and qualitatively reproduces the local MP2 potential energy surface of the parallel-displaced benzene dimer. This method was further critically compared to high-level calculations recently reported in the literature for a range of pi-stacked complexes, including monosubstituted benzene-benzene dimers, along with DNA and RNA bases, and generally agrees with MP2 and/or CCSD(T) results to within +/-2 kJ mol(-1). We also show that the resulting BH&H binding energy is closely related to the electron density in the intermolecular region. The net result is that the BH&H functional, presumably due to fortuitous cancellation of errors, provides a pragmatic, computationally efficient quantum mechanical tool for the study of large pi-stacked systems such as DNA.

Ab initio and density functional calculations are employed to investigate the role of hydrogen bonding in the binding of cisplatin to the purine bases guanine and adenine. Through the use of the theory of atoms in molecules (AIM), it is shown that hydrogen bonds are ubiquitous in such systems, with N-H...N and N-H...Cl interactions present in addition to the expected N-H...O. This in turn means that the known stability of cisplatin-guanine complexes cannot be ascribed solely to hydrogen bonding and allows decomposition of total binding energy into contributions from covalent and hydrogen bonds. To do so, a new method for predicting hydrogen bond energies from bond critical point properties is proposed, employing partial least-squares analysis to remove the family dependence of simple models. Still more hydrogen bond motifs are found in bifunctional complexes of the general type purine-[Pt(NH(3))(2)](2+)-purine, including purine...purine contacts, though again the energetics of these are insufficient to explain the observed trends in stability. Finally, the effect of platination on the pairing of guanine with cytosine is studied in a similar manner, revealing large redistributions of hydrogen bonding but surprisingly small overall changes in pairing energy.

Multi-core oxomanganese complexes can adopt different oxidation states and protonation patterns depending on ligands and external conditions (for example, solvent, pH, and redox potential). An archetypical example of such complexes is the Mn4Ca cluster in the oxygen-evolving complex (OEC) of photosystem II (PSII). Despite the recent high-resolution crystal structure of PSII, some uncertainty about the oxidation state of the Mn centers and the protonation pattern of the oxygen atoms bridging the metals still exists. In this work, we construct a quantum-chemically based tool to “recognize” the oxidation state and the protonation pattern of oxomanganese complexes from their experimental structure. Combined with simple structural information, our tool can be employed as an empirical guideline to recognize the oxidation state and/or the protonation pattern of those oxomanganese complexes for which this information is not experimentally available.

Over the past 10 years, anion–π interaction has been recognized as an important weak force that may occur between anionic systems and electron- deficient aromatics. Lately, this supramolecular contact has experienced a rapidly growing interest, as reflected by numerous recent literature reports. The present paper highlights the tremendous progress achieved in the field by emphasizing three important studies involving anion–π interactions published in 2010. In addition, a pioneering search of the Protein Data Bank (PDB) reveals short anion–π contacts in some protein structures.

In the family of respiratory proteins, hemoglobins and myoglobins have been the first to be crystallized in ‘50. Despite the availability of 3D structures, issues regarding the microscopic functioning remain open, such as, for instance, the R to T switching mechanism in hemoglobin or the ligand escape process in myoglobin. Due to the relatively small number of residues, myoglobin is the suitable candidate to investigate the more general structure-function paradigm, being defined as the hydrogen atom of biology. In this work, to complement our recent study on the dynamics of internal cavities of myoglobin[1], the effect of solvation on these intrinsic pathways has been explored. In particular, 60ns-long molecular dynamics simulation of horse heart met-myoglobin was further analyzed and the dynamics of waters residing around/inside the protein with average residence times of up to tens of nanoseconds was monitored. Together with the knowledge obtained previously[1], the analysis of solvent revealed that myoglobin has in fact only few stable hydration sites in which a water molecule can stay for time longer than 2 ns. Strikingly, all of these sites are close to protein/solvent portals observed in previous studies focused on the entry/escape and migration of various ligands in myoglobin[2-4].1. Scorciapino, M. A.; Robertazzi, A.; Casu, M.; Ruggerone, P.; Ceccarelli, M. J. Am. Chem. Soc. 2009, 131, 11825-11832.2. Cohen, J.; Arkhipov, A.; Braun, R.; Schulten, K. Biophys. J. 2006, 91, 1844-1857.3. Ruscio, J. Z.; Kumar, D.; Shukla, M.; Prisant, M. G.; Murali, T. M.; Onufriev, A. V. Proc. Natl. Acad. Sci. USA 2008, 105, 9204-9209.4. Ceccarelli, M.; Anedda, R.; Casu, M.; Ruggerone, P. Proteins 2008, 71, 1231-1236.

Copper complexes of 1,10-phenanthroline (phen) are chemical nucleases employed as footprinting reagents for determining ligand binding sites. The cleavage activity of the parent complex, Cu(phen)2, occurs according to the following mechanism: a) reduction of Cu(phen)22+ to Cu(phen)2+; b) non-coordinative binding of Cu(phen)2+ to DNA; c) Cu(phen)2+ oxidation to Cu(phen)22+ by H2O2, and formation of Cu-“oxo” and/or Cu-“hydroxyl” species; d) oxidative attack leading to DNA-cleavage.However, the potential clinical use of the parent compound is mainly prevented by two drawbacks: i) the low binding constant of the second phenanthroline; ii) the modest sequence selective DNA cleavage.To improve Cu(phen)2 efficiency, Pitie et al. used a serinol bridge to link the two phen rings leading to Cu(2-Clip-phen) and Cu(3-Clip-phen) derivatives, which cleave the DNA 2 and 60 times more efficiently than Cu(phen)2. To address the modest sequence selectivity, the amine group of the serinol bridge was functionalized with sequence specific DNA minor/major-groove binding ligands such as cisplatin- and distamycin-like compounds, leading to encouraging results.In this work, a combination of theoretical methods, including DFT, Docking and Molecular Dynamics, was employed to i) characterize the DNA binding of these complexes and ii) to determine the origin of their diverse DNA-cleavage efficiency. Our simulations clearly revealed that several factors such as planarity of the ligand, better interaction with DNA and minor-groove fit, contribute to the enhanced efficiency of Cu(3-Clip-phen) compared to the other structurally similar complexes.

The crystal lattice of the three isostructural compounds , (C(6)H(8)N(2)H)(2)[M(C(3)H(2)O(4))(2)(H(2)O)(2)].4H(2)O (C(6)H(8)N(2)H = protonated 2-amino-4-picoline, M = Ni/Co/Mn, C(3)H(4)O(4) = malonate dianion; hereafter, malonate) is formed by supramolecular 2D layers. Hydrogen-bonding, pi...pi and lone pair...pi interactions play crucial role in organizing monomeric [M(II)(mal)(2)(H(2)O)(2)] units into 2D sheets along the ab plane, through the self-association between two different supramolecular building blocks, namely a tetrameric water cluster including metal-coordinated water molecules, and R(2)(2)(8) and R(2)(2)(7) hydrogen-bonded recognition synthons between 2-amino-4-picolinium and malonate. DFT calculations clearly show that the robust 2-amino-4-picolinium/malonate hydrogen-bonded motif drives the self-assembly of the supramolecular network observed.

In the family of respiratory proteins, hemoglobins and myoglobins have been the first to be crystallized in '50. Despite their precise 3D structures are available at high resolution, some questions regarding the microscopic functioning remain yet open. The R to T switching mechanism in hemoglobins and the ligand escape process in myoglobins remain still under debate.Thanks to the small size, myoglobin is the preferred candidate also for the more general structure-funcion paradigm. In the interior of myoglobin five main docking sites have been identified, especially with Xe NMR, and for long time these Xenon cavities have been classified as packing defects. Recently, it was shown that they might be involved in ligands migration path, even if mechanisms used by myoglobin to connect these cavities is still unknown as well as processes regulating its biologic functions. In this work we made use of standard MD simulations of solvated myoglobin to characterize internal cavities. Our principal results is that we have found several secondary cavities showing volume and occurrence at least comparable to that of Xenon cavities.In order to rationalize and in-depth analyze such a huge amount of data (ca. 30000 cavities/10 ns MD), special cluster-analysis was applied: we classified all cavities with respect to the position, size and occurrence as function of simulation time ascribing them to different clusters. This analysis implicitly highlights possible ligand migration paths for small ligands within the protein matrix allowing to quantitatively compare dynamical behaviour of different myoglobins towards different ligands. Our suggestion that the secondary cavities constitute the preferred path for ligand escape is also supported by explicit metadynamics simulations of ligand escape.