Application of molecular dynamic simulations in modeling the excited state behavior of confined molecules.

Relative to isotropic organic solvent medium, the structure and conformation of a reactant molecule in an organized and confining medium are often different. In addition, because of the rigidity of the immediate environment, the reacting molecule have a little freedom to undergo large changes even upon gaining energy or modifications in the electronic structure. These alterations give rise to differences in the photochemistry of a molecular and supramolecular species. In this study, one such example is presented. α-Alkyl dibenzylketones upon excitation in isotropic solvents give products via Norrish type I and type II reactions that are independent of the chain length of the alkyl substituent. On the other hand, when these molecules are enclosed within an organic capsule of volume ~ 550 Å3, they give products that are strikingly dependent on the length of the α-alkyl substitution. These previously reported experimental observations are rationalized based on the structures generated by molecular modeling (docking and molecular dynamics (MD) simulations). It is shown that MD simulations that are utilized extensively in biologically important macromolecules can also be useful to understand the excited state behavior of reactive molecules that are part of supramolecular assemblies. These simulations can provide structural information of the reactant molecule and the surroundings complementing that with the one obtained from 1 and 2D NMR experiments. MD simulated structures of seven α-alkyl dibenzylketones encapsulated within the octa acid capsule provide a clear understanding of their unique behavior in this restricted medium. Because of the rigidity of the medium, these structures although generated in the ground state can rationalize the photochemical behavior of the molecules in the excited state.

Discovery of SARS-CoV-2 Inhibitors Featuring Novel Histidine α-Nitrile Motif.

As COVID-19 infection caused severe public health concerns recently, the development of novel antivirals has become the need of the hour. Main protease (Mpro ) has been an attractive target for antiviral drugs since it plays a vital role in polyprotein processing and virus maturation. Herein we report the discovery of a novel class of inhibitors against the SARS-CoV-2, bearing histidine α-nitrile motif embedded on a simple dipeptide framework. In-vitro and in-silico studies revealed that the histidine α-nitrile motif envisioned to target the Mpro contributes to the inhibitory activity. Among a series of dipeptides synthesized featuring this novel structural motif, some dipeptides displayed strong viral reduction (EC50 =0.48 µM) with a high selectivity index, SI>454.54. These compounds also exhibit strong binding energies in the range of -28.7 to -34.2 Kcal/mol. The simple dipeptide structural framework, amenable to quick structural variations, coupled with ease of synthesis from readily available commercial starting materials are the major attractive features of this novel class of SARS-CoV-2 inhibitors. The histidine α-nitrile dipeptides raise the hope of discovering potent drug candidates based on this motif to fight the dreaded SARS-CoV-2.

Promiscuous Catalytic Activity of a Binuclear Metallohydrolase: Peptide and Phosphoester Hydrolyses.

In this study, chemical promiscuity of a binuclear metallohydrolase Streptomyces griseus aminopeptidase (SgAP) has been investigated using DFT calculations. SgAP catalyzes two diverse reactions, peptide and phosphoester hydrolyses, using its binuclear (Zn-Zn) core. On the basis of the experimental information, mechanisms of these reactions have been investigated utilizing leucine p-nitro aniline (Leu-pNA) and bis(4-nitrophenyl) phosphate (BNPP) as the substrates. The computed barriers of 16.5 and 16.8 kcal/mol for the most plausible mechanisms proposed by the DFT calculations are in good agreement with the measured values of 13.9 and 18.3 kcal/mol for the Leu-pNA and BNPP hydrolyses, respectively. The former was found to occur through the transfer of two protons, while the latter with only one proton transfer. They are in line with the experimental observations. The cleavage of the peptide bond was the rate-determining process for the Leu-pNA hydrolysis. However, the creation of the nucleophile and its attack on the electrophile phosphorus atom was the rate-determining step for the BNPP hydrolysis. These calculations showed that the chemical nature of the substrate and its binding mode influence the nucleophilicity of the metal bound hydroxyl nucleophile. Additionally, the nucleophilicity was found to be critical for the Leu-pNA hydrolysis, whereas double Lewis acid activation was needed for the BNPP hydrolysis. That could be one of the reasons why peptide hydrolysis can be catalyzed by both mononuclear and binuclear metal cofactors containing hydrolases, while phosphoester hydrolysis is almost exclusively by binuclear metallohydrolases. These results will be helpful in the development of versatile catalysts for chemically distinct hydrolytic reactions.

Structure-Activity Relationship of Carbon Nitride Dots in Inhibiting Tau Aggregation.

Due to the numerous failed clinical trials of anti-amyloid drugs, microtubule associated protein tau (MAPT) now stands out as one of the most promising targets for AD therapy. In this study, we report for the first time the structure-dependent MAPT aggregation inhibition of carbon nitride dots (CNDs). CNDs have exhibited great promise as a potential treatment of Alzheimer's disease (AD) by inhibiting the aggregation of MAPT. In order to elucidate its structure-activity relationship, CNDs were separated via column chromatography and five fractions with different structures were obtained that were characterized by multiple spectroscopy methods. The increase of surface hydrophilic functional groups is consistent with the increase of polarity from fraction 1 to 5. Particle sizes (1-2 nm) and zeta potentials (~-20 mV) are similar among five fractions. With the increase of polarity from fraction 1 to 5, their MAPT aggregation inhibition capacity was weakened. This suggests hydrophobic interactions between CNDs and MAPT, validated via molecular dynamics simulations. With a zebrafish blood-brain barrier (BBB) model, CNDs were observed to cross the BBB through passive diffusion. CNDs were also found to inhibit the generation of multiple reactive oxygen species, which is an important contributor to AD pathogenesis.

Dynamics of Anthracene Excimer Formation within a Water-Soluble Nanocavity at Room Temperature.

Excited anthracene is well-known to photodimerize and not to exhibit excimer emission in isotropic organic solvents. Anthracene (AN) forms two types of supramolecular host-guest complexes (2:1 and 2:2, H:G) with the synthetic host octa acid in aqueous medium. Excitation of the 2:2 complex results in intense excimer emission, as reported previously, while the 2:1 complex, as expected, yields only monomer emission. This study includes confirming of host-guest complexation by NMR, probing the host-guest structure by molecular dynamics simulation, following the dynamics AN molecules in the excited state by ultrafast time-resolved experiments, and mapping of the excited surface through quantum chemical calculations (QM/MM-TDDFT method). Importantly, time-resolved emission experiments revealed the excimer emission maximum to be time dependent. This observation is unique and is not in line with the textbook examples of time-independent monomer-excimer emission maxima of aromatics in solution. The presence of at least one intermediate between the monomer and the excimer is inferred from time-resolved area normalized emission spectra. Potential energy curves calculated for the ground and excited states of two adjacent anthracene molecules via the QM/MM-TDDFT method support the model proposed on the basis of time-resolved experiments. The results presented here on the excited-state behavior of a well-investigated aromatic molecule, namely the parent anthracene, establish that the behavior of a molecule drastically changes under confinement. The results presented here have implications on the behavior of molecules in biological systems.

Degradation of a Main Plastic Pollutant Polyethylene Terephthalate by Two Distinct Proteases (Neprilysin and Cutinase-like Enzyme).

In this DFT study, hydrolysis of polyethylene terephthalate (PET), a major cause of plastic pollution, by two distinct enzymes, neprilysin (NEP, a mononuclear metalloprotease) and cutinase-like enzyme (CLE, a serine protease), has been investigated. These enzymes utilize different mechanisms for the degradation of PET. NEP uses either the metal-bound hydroxide attack (MH) mechanism or reverse protonation (RP) mechanism, while CLE utilizes a general acid/base mechanism that includes acylation and deacylation processes. Additionally, the RP mechanism of NEP can proceed through three pathways, RP0, RP1, and RP2. The DFT calculations predict that, among all these mechanisms, the MH mechanism is the energetically most favorable one for the NEP enzyme. In comparison, CLE catalyzes this reaction with a significantly higher barrier. These results suggest that the Lewis acid and nucleophile activations provided by the Zn metal center of NEP are more effective than the hydrogen bonding interactions afforded by the catalytic Ser85-His180-Asp165 triad of CLE. They have provided intrinsic details regarding PET degradation and will pave the way for the design of efficient metal-based catalysts for this critical reaction.

Hydrolysis of chemically distinct sites of human serum albumin by polyoxometalate: A hybrid QM/MM (ONIOM) study.

In this study, mechanisms of hydrolysis of all four chemically diverse cleavage sites of human serum albumin (HSA) by [Zr(OH)(PW11 O39 )]4- (ZrK) have been investigated using the hybrid two-layer QM/MM (ONIOM) method. These reactions have been proposed to occur through the following two mechanisms: internal attack (IA) and water assisted (WA). In both mechanisms, the cleavage of the peptide bond in the Cys392-Glu393 site of HSA is predicted to occur in the rate-limiting step of the mechanism. With the barrier of 27.5 kcal/mol for the hydrolysis of this site, the IA mechanism is found to be energetically more favorable than the WA mechanism (barrier = 31.6 kcal/mol). The energetics for the IA mechanism are in line with the experimentally measured values for the cleavage of a wide range of dipeptides. These calculations also suggest an energetic preference (Cys392-Glu393, Ala257-Asp258, Lys313-Asp314, and Arg114-Leu115) for the hydrolysis of all four sites of HSA. © 2018 Wiley Periodicals, Inc.

Investigating coordination flexibility of glycerophosphodiesterase (GpdQ) through interactions with mono-, di-, and triphosphoester (NPP, BNPP, GPE, and paraoxon) substrates.

In this study, interactions of the catalytically active binuclear form of glycerophosphodiesterase (GpdQ) with four chemically diverse substrates, i.e. NPP (a phosphomonoester), BNPP and GPE (both phosphodiesters), and paraoxon (a phosphotriester) have been investigated using all-atom molecular dynamics (MD) simulations. The roles of metal ions and key amino acid residues, coordination flexibility, and dynamic transformations in all enzyme-substrate complexes have been elucidated. The roles of important first and second coordination shell residues in substrate binding and coordination flexibility of the enzyme suggested by simulations are supported by experimental data. The chemical nature of the substrate is found to influence the mode of binding, electrostatic surface potential, metal-metal distance, and reorganization of the active site. The experimentally proposed association between the substrate binding and coordination flexibility is analyzed using principal component analysis (PCA), movements of loops, and root-mean-square-fluctuations (RMSF) as parameters. The PCA of these substrates provides different energy basins, i.e. one, three, two and five for NPP, BNPP, GPE, and paraoxon, respectively. Additionally, the area of an irregular hexagon (268.3, 288.9, 350.8, and 362.5 Å2) formed by the residues on these loops illustrates their distinct motions. The substrate binding free energies of NPP, BNPP, and GPE are quite close (22.4-24.3 kcal mol-1), but paraoxon interacts with the smallest binding free energy (14.1 kcal mol-1). The metal binding energies in the presence of these substrates are substantially different, i.e. the lowest for NPP and the highest for paraoxon. These results thus provide deeper insight into the chemical promiscuity and coordination flexibility of this important enzyme.

Room-Temperature Phosphorescence from Encapsulated Pyrene Induced by Xenon.

Phosphorescence from pyrene especially at room temperature is uncommon. This emission was recorded utilizing a supramolecular organic host and the effect due to the heavy atom. Poor intersystem crossing from S1 to T1, small radiative rate constant from T1, and large rate constant for oxygen quenching hinder the phosphorescence of aromatic molecules at room temperature in solution. In this study, these limitations are overcome by encapsulating a pyrene molecule within a water-soluble capsule (octa acid, OA) and purging with xenon. While OA suppressed oxygen quenching, xenon enabled the intersystem crossing from S1 to T1 and radiative process from T1 to S0 through the well-known heavy atom effect. The close interaction facilitated between the pyrene and the heavy atom perturber xenon in the three-component supramolecular assembly (OA, pyrene, and xenon) resulted in phosphorescence from pyrene. Computational modeling and NMR studies supported the postulate that pyrene and more than one molecule of xenon are present within a confined space of the OA capsule.

Ultrafast Solvation Dynamics Reveal that Octa Acid Capsule's Interior Dryness Depends on the Guest.

Coumarins are well-known to exhibit environment-dependent excited-state behavior. We have exploited this feature to probe the accessibility of solvent water molecules to coumarins (guest) encapsulated within an organic capsule (host). Two sets of coumarins, one small that fits well within the capsule and the other larger that fits within an enlarged capsule, are used as guests. In our study, the two sets of coumarins serve different purposes: one is employed to explore electron transfer across the capsule and the other to release photoprotected acids into the aqueous environment. The capsule is made up of two molecules of octa acid (OA) and is soluble in an aqueous medium under slightly basic conditions. Molecular modeling studies revealed that while the OA capsule is fully closed with no access to water in the case of smaller coumarins, with the larger molecules, the capsule is not tight and the guest is in contact with water molecules, the number being dependent on the size of the coumarin. We have used the ultrafast time-dependent Stokes shift method to understand the solvent dynamics around the above guest molecules encapsulated within an OA capsule in an aqueous medium. Results depict that for the smaller sets of coumarins, water cannot access the guests within the OA cavity during their excited state lifetime. However, the case is completely different for the larger coumaryl esters. Distorted capsule structure exposes the guest to water, and a dynamics Stokes shift is observed. The average solvation time decreases with the increasing size of guests that clearly indicates accessibility of the encapsulated guests toward greater number of water molecules as the capsule structure distorts with increasing size of the guests. Results of the ultrafast solvation dynamics are consistent with that of molecular dynamics simulation.

Ultrafast trans → cis Photoisomerization Dynamics of Alkyl-Substituted Stilbenes in a Supramolecular Capsule.

Ultrafast spectroscopy reveals the effects of confinement on the excited-state photoisomerization dynamics for a series of alkyl-substituted trans-stilbenes encapsulated in the hydrophobic cavity of an aqueous supramolecular organic host-guest complex. Compared with the solvated compounds, encapsulated trans-stilbenes have broader excited-state absorption spectra, excited-state lifetimes that are 3-4 times longer, and photoisomerization quantum yields that are 1.7-6.5 times lower in the restricted environment. The organic capsule disrupts the equilibrium structure and restricts torsional rotation around the central C═C double bond in the excited state, which is an important motion for the relaxation of trans-stilbene from S1 to S0. The location and identity of alkyl substituents play a significant role in determining the excited-state dynamics and photoisomerization quantum yields by tuning the relative crowding inside the capsule. The results are discussed in terms of distortions of the ground- and excited-state potential energy surfaces, including the topology of the S1-S0 conical intersection.

Structural and Mechanistic Insights into Development of Chemical Tools to Control Individual and Inter-Related Pathological Features in Alzheimer's Disease.

To elucidate the involvement of individual and inter-related pathological factors [i.e., amyloid-ß (Aß), metals, and oxidative stress] in the pathogenesis of Alzheimer's disease (AD), chemical tools have been developed. Characteristics required for such tool construction, however, have not been clearly identified; thus, the optimization of available tools or new design has been limited. Here, key structural properties and mechanisms that can determine tools' regulatory reactivities with multiple pathogenic features found in AD are reported. A series of small molecules was built up through rational structural selection and variations onto the framework of a tool useful for in vitro and in vivo metal-Aß investigation. Variations include: (i) location and number of an Aß interacting moiety; (ii) metal binding site; and (iii) denticity and structural flexibility. Detailed biochemical, biophysical, and computational studies were able to provide a foundation of how to originate molecular formulas to devise chemical tools capable of controlling the reactivities of various pathological components through distinct mechanisms. Overall, this multidisciplinary investigation illustrates a structure-mechanism-based strategy of tool invention for such a complicated brain disease.

Effects of Ligand Environment in Zr(IV) Assisted Peptide Hydrolysis.

In this DFT study, activities of 11 different N2O4, N2O3, and NO2 core containing Zr(IV) complexes, 4,13-diaza-18-crown-6 (I'N2O4), 1,4,10-trioxa-7,13-diazacyclopentadecane (I'N2O3), and 2-(2-methoxy)ethanol (I'NO2), respectively, and their analogues in peptide hydrolysis have been investigated. Based on the experimental information, these molecules were created by altering protonation states (singly protonated, doubly protonated, or doubly deprotonated) and number of their ligands. The energetics of the I'N2O4, and I'NO2 and their analogues predicted that both stepwise and concerted mechanisms occurred either with similar barriers, or the latter was more favorable than the former. They also showed that the doubly deprotonated form hydrolyzed the peptide bond with substantially lower barriers than the barriers for other protonation states. For NO2 core possessing complexes, Zr-(NO2)(OHH)(H2O/OH)n for n = 1-3, the hydroxyl group containing molecules were found to be more reactive than their water ligand possessing counterparts. The barriers for these complexes reduced with an increase in the coordination number (6-8) of the Zr(IV) ion. Among all 11 molecules, the NO2 core possessing and two hydroxyl group containing I'DNO2-2H complex was found to be the most reactive complex with a barrier of 28.9 kcal/mol. Furthermore, barriers of 27.5, 28.9, and 32.0 kcal/mol for hydrolysis of Gly-Glu (negative), Gly-Gly (neutral), and Gly-Lys (positive) substrates, respectively, by this complex were in agreement with experiments. The activities of these complexes were explained in terms of basicity of their ligand environment and nucleophilicity of the Zr(IV) center using metal-ligand distances, charge on the metal ion, and the metal-nucleophile distance as parameters. These results provide a deeper understanding of the functioning of these complexes and will help design Zr(IV)-based synthetic metallopeptidases.

Theoretical insights into the functioning of metallopeptidases and their synthetic analogues.

CONSPECTUS: The selective hydrolysis of a peptide or amide bond (-(O═)C-NH-) by a synthetic metallopeptidase is required in a wide range of biological, biotechnological, and industrial applications. In nature, highly specialized enzymes known as proteases and peptidases are used to accomplish this daunting task. Currently, many peptide bond cleaving enzymes and synthetic reagents have been utilized to achieve efficient peptide hydrolysis. However, they possess some serious limitations. To overcome these inadequacies, a variety of metal complexes have been developed that mimic the activities of natural enzymes (metallopeptidases). However, in comparison to metallopeptidases, the hydrolytic reactions facilitated by their existing synthetic analogues are considerably slower and occur with lower catalytic turnover. This could be due to the following reasons: (1) they lack chemical properties of amino acid residues found within enzyme active sites; (2) they contain a higher metal coordination number compared with naturally occurring enzymes; and (3) they do not have access to second coordination shell residues that provide substantial rate enhancements in enzymes. Additionally, the critical structural and mechanistic information required for the development of the next generation of synthetic metallopeptidases cannot be readily obtained through existing experimental techniques. This is because most experimental techniques cannot follow the individual chemical steps in the catalytic cycle due to the fast rate of enzymes. They are also limited by the fact that the diamagnetic d(10) Zn(II) center is silent to electronic, electron spin resonance, and (67)Zn NMR spectroscopies. Therefore, we have employed molecular dynamics (MD), quantum mechanics (QM), and hybrid quantum mechanics/molecular mechanics (QM/MM) techniques to derive this information. In particular, the role of the metal ions, ligands, and microenvironment in the functioning of mono- and binuclear metal center containing enzymes such as insulin degrading enzyme (IDE) and bovine lens leucine aminopeptidase (BILAP), respectively, and their synthetic analogues have been investigated. Our results suggested that in the functioning of IDE, the chemical nature of the peptide bond played a role in the energetics of the reaction and the peptide bond cleavage occurred in the rate-limiting step of the mechanism. In the cocatalytic mechanism used by BILAP, one metal center polarized the scissile peptide bond through the formation of a bond between the metal and the carbonyl group of the substrate, while the second metal center delivered the hydroxyl nucleophile. The Zn(N3) [Zn(His, His, His)] core of matrix metalloproteinase was better than the Zn(N2O) [Zn(His, His, Glu)] core of IDE for peptide hydrolysis. Due to the synergistic interaction between the two metal centers, the binuclear metal center containing Pd2(µ-OH)([18]aneN6)](4+) complex was found to be ∼100 times faster than the mononuclear [Pd(H2O)4](2+) complex. A successful small-molecule synthetic analogue of a mononuclear metallopeptidase must contain a metal with a strong Lewis acidity capable of reducing the pKa of its water ligand to less than 7. Ideally, the metal center should include three ligands with low basicity. The steric effects or strain exerted by the microenvironment could be used to weaken the metal-ligand interactions and increase the activity of the metallopeptidase.

Structural and Material Properties of Amyloid Aß40/42 Fibrils.

In this study, structural and mechanical properties of a series of models of Aß42 (one- and two-fold) and Aß40 (two- and three-fold) fibrils have been computed by using all-atom molecular dynamics simulations. Based on calculations of the twist angle (θ) and periodicity (v=360d/θ), oligomers formed by 20, 11, and 13 monomers were found to be the smallest realistic models of three-fold Aß40 , one-fold Aß42 , and two-fold Aß42 fibrils, respectively. Our results predict that the Aß40 fibrils initially exist in two staggered conformations [STAG(+2) and STAG(+1)] and then undergo a [STAG(+2)→STAG(+1)] transformation in a size-dependent manner. The length of the loop region consisting of the residues 23-29 shrinks with the elongation of both Aß40 and Aß42 fibrils. A comparison of the computed potential energy suggests that a two-fold Aß40 aggregate is more stable than its three-fold counterpart, and that Aß42 oligomers can exist only in one-fold conformation for aggregates of more than 11 monomers in length. The computed Young's modulus and yield strengths of 50 GPa and 0.95 GPa, respectively, show that these aggregates possess excellent material properties.

Mechanisms of peptide hydrolysis by aspartyl and metalloproteases.

Peptide hydrolysis has been involved in a wide range of biological, biotechnological, and industrial applications. In this perspective, the mechanisms of three distinct peptide bond cleaving enzymes, beta secretase (BACE1), insulin degrading enzyme (IDE), and bovine lens leucine aminopeptidase (BILAP), have been discussed. BACE1 is a catalytic Asp dyad [Asp, Asp-] containing aspartyl protease, while IDE and BILAP are mononuclear [Zn(His, His, Glu)] and binuclear [Zn1(Asp, Glu, Asp)-Zn2(Lys, Glu, Asp, Asp)] core possessing metallopeptidases, respectively. Specifically, enzyme-substrate interactions and the roles of metal ion(s), the ligand environment, second coordination shell residues, and the protein environment in the functioning of these enzymes have been elucidated. This information will be useful to design small inhibitors, activators, and synthetic analogues of these enzymes for biomedical, biotechnological, and industrial applications.

Cooperative Self-Assembly of a Quaternary Complex Formed by Two Cucurbit[7]uril Hosts, Cyclobis(paraquat-p-phenylene), and a "Designer" Guest.

The self-assembly in aqueous solution of the well-known cyclophane, cyclobis(paraquat-p-phenylene) (BB(4+) ), and two cucurbit[7]uril (CB7) hosts around a simple hydroquinol-based, diamine guest (GH2 (2+) ) was investigated by (1) H NMR and electronic absorption spectroscopies, electrospray mass spectrometry and DFT computations. The formation of a quaternary supramolecular assembly [GH2 (2+) ⋅BB(4+) ⋅ (CB7)2 ] was shown to be a very efficient process, which takes place not only because of the attractive forces between each of the hosts and the guest, but also because of the lateral interactions between the hosts in the final assembly. This complementary set of attractive interactions results in clear cooperative binding effects that help overcome the entropic barriers for multiple component assembly.

A Redox-Active, Compact Molecule for Cross-Linking Amyloidogenic Peptides into Nontoxic, Off-Pathway Aggregates: In Vitro and In Vivo Efficacy and Molecular Mechanisms.

Chemical reagents targeting and controlling amyloidogenic peptides have received much attention for helping identify their roles in the pathogenesis of protein-misfolding disorders. Herein, we report a novel strategy for redirecting amyloidogenic peptides into nontoxic, off-pathway aggregates, which utilizes redox properties of a small molecule (DMPD, N,N-dimethyl-p-phenylenediamine) to trigger covalent adduct formation with the peptide. In addition, for the first time, biochemical, biophysical, and molecular dynamics simulation studies have been performed to demonstrate a mechanistic understanding for such an interaction between a small molecule (DMPD) and amyloid-ß (Aß) and its subsequent anti-amyloidogenic activity, which, upon its transformation, generates ligand-peptide adducts via primary amine-dependent intramolecular cross-linking correlated with structural compaction. Furthermore, in vivo efficacy of DMPD toward amyloid pathology and cognitive impairment was evaluated employing 5xFAD mice of Alzheimer's disease (AD). Such a small molecule (DMPD) is indicated to noticeably reduce the overall cerebral amyloid load of soluble Aß forms and amyloid deposits as well as significantly improve cognitive defects in the AD mouse model. Overall, our in vitro and in vivo studies of DMPD toward Aß with the first molecular-level mechanistic investigations present the feasibility of developing new, innovative approaches that employ redox-active compounds without the structural complexity as next-generation chemical tools for amyloid management.

Role of hydrogen bonds in molecular packing of photoreactive crystals: templating photodimerization of protonated stilbazoles in crystalline state with a combination of water molecules and chloride ions.

A difference in photobehavior and molecular packing between hydrated and anhydrous crystals of protonated trans-stilbazoles has been identified. While stilbazoles are not photoreactive in the crystalline state, upon protonation with HCl in the solid state they dimerized to a single dimer (anti-head-tail) when exposed to UV light. In these photoreactive crystals the protonated stilbazole molecules are arranged in a ladder-like format with the rungs made up of water molecules and chloride ions. A combination of water and chloride ion holds the protonated trans-stilbazoles through either N-HO or N-HCl(-) interactions. Anhydrous protonated stilbazole crystals prepared by heating the 'wet' crystals under reduced pressure were inert upon exposure to UV light. As per X-ray crystal structure analyses these light stable crystals did not contain water molecules in their lattice. The current investigation has established that water molecules are essential for photodimerization of crystalline protonated trans-stilbazoles. To compare the reactivity of protonated trans-stilbazoles with that of protonated cis-stilbazoles, photoreactivity and packing arrangement of cis-4-iodo stilbazole·HCl salt was examined. This molecule in the crystalline state only isomerized to the trans isomer and did not dimerize. Thus, while the trans isomer dimerized and did not isomerize, the cis isomer only isomerized and did not dimerize in the crystalline state. To probe the role of cationπ interaction in the packing of protonated trans-stilbazoles, energies of various types of packing in the gas phase were estimated by MP-2 calculations and cationπ interaction was found to be unimportant in the packing of protonated trans-stilbazole crystals investigated here.

Structural studies of catalytic peptides using molecular dynamics simulations.

Many self-assembling peptides can form amyloid like structures with different sizes and morphologies. Driven by non-covalent interactions, their aggregation can occur through distinct pathways. Additionally, they can bind metal ions to create enzyme like active sites that allow them to catalyze diverse reactions. Due to the non-crystalline nature of amyloids, it is quite challenging to elucidate their structures using experimental spectroscopic techniques. In this aspect, molecular dynamics (MD) simulations provide a useful tool to derive structures of these macromolecules in solution. They can be further validated by comparing with experimentally measured structural parameters. However, these simulations require a multi-step process starting from the selection of the initial structure to the analysis of MD trajectories. There are multiple force fields, parametrization protocols, equilibration processes, software and analysis tools available for this process. Therefore, it is complicated for non-experts to select the most relevant tools and perform these simulations effectively. In this chapter, a systematic methodology that covers all major aspects of modeling of catalytic peptides is provided in a user-friendly manner. It will be helpful for researchers in this critical area of research.