Crystal Packing Interactions Research Articles

Discovery of a Series of Macrocycles as Potent Inhibitors of Leishmania Infantum.

Macrocycles are prominent among drugs for treatment of infectious disease, with many originating from natural products. Herein we report on the discovery of a series of macrocycles structurally related to the natural product hymenocardine. Members of this series were found to inhibit the growth of Plasmodium falciparum, the parasite responsible for most malaria cases, and of four kinetoplastid parasites. Notably, macrocycles more potent than miltefosine, the only oral drug used for the treatment of the neglected tropical disease visceral leishmaniasis, were identified in a phenotypic screen of Leishmania infantum. In vitro profiling highlighted that potent inhibitors had satisfactory cell permeability with a low efflux ratio, indicating their potential for oral administration, but low solubility and metabolic stability. Analysis of predicted crystal structures suggests that optimization should focus on the reduction of π-π crystal packing interactions to reduce the strong crystalline interactions and improve the solubility of the most potent lead.

Cobalt(II) Complex Constructed from Pyrazinecarboxamide and Aromatic Carboxylic Acid: Synthesis, Single Crystal XRD Along with Computational Study

A cobalt (II) mononuclear complex was synthesized by two-nitrobenzoic acid and pyrazine-two- carboxamide ligands in the presence of sodium bicarbonate and aqueous solution of cobalt acetate tetrahydrate. The synthesized cobalt(II) complex was characterized by single crystal X-rays diffraction. The coordination geometry of the cobalt complex was octahedral with water molecules occupying the axial sites. A lot of intermolecular interactions were in response to stabilize the supramolecular assembly which were inspected by Hirshfeld surface analysis. Enrichment ratios were calculated to find the pair of atoms having the highest propensity to form crystal packing interactions. Void analysis was conducted to forecast how the crystal would respond to applied stress. Interaction energy calculations were carried out using the B3LYP/6-31G(d,p) electron density model to identify which energy types most significantly contributed to the supramolecular assembly. Moreover, the energy data obtained from DFT calculations showed an average level of stability of the molecule. The moderate HOMO-LUMO energy gap suggested reactivity, while a high electrophilicity index indicates a strong tendency for electron-accepting reactions.

Structural Investigation and Hirshfeld Surface Analysis of 2-6-Dimethoxy-4-((2-Nitrophenylimin)Methyl)Phenol

Introduction: The reaction between 4-hydroxy-3,5-dimethoxyenzaldehyde and 2-ni-troaniline has been discovered, and the final product has been identified such as 2-6-dimethoxy-4-((2-nitrophenylimin)methyl)phenol (C1). METHOD: X-ray diffraction examination per-formed on a single crystal provided conclusive evidence regarding the structure. Crystallography reveals that the two molecules A and B that were enclosed within the asymmetric unit are struc-turally distinct from one another. C-H···O, N-H···O, and O-H···O bonding is primarily respon-sible for the crystal packing stability. H-O and off-set stacking interactions also contribute to the crystal packing's overall stability. Results: To do further research into the intermolecular interactions, the Hirshfeld surface analy-sis technique is utilized. It is possible to determine the partiality of the interatomic contacts to create crystal packing interactions by computing the improvement ratio for those contacts. In addition, computational research is carried out with the B3LYP/6-31G(d,p) model to determine the amount of energy that is required for molecular pairs to interact. Conclusion: The study concluded the roles those different kinds of interaction energy play in maintaining the stability of the molecular pair.

Synthesis and crystal structures of disubstituted ferrocenes carrying bromo and N-heteroaryl substituents

Noncovalent interactions in crystal packing play significant roles in the formation of extended network structures. Thus, this study aims to investigate the influence of noncovalent bonds, particularly halogen bonds, on the crystal packing of ferrocene derivatives. For this purpose, disubstituted ferrocene derivatives carrying both bromo and N-heteroaryl substituents, 1‑bromo-1ʹ-(Het)ferrocene [Het = 5-pyrimidyl (1), 2-pyridyl (2), and 4-pyridyl (3)] and 1‑bromo-2-(Het)ferrocene [Het = 5-pyrimidyl (4) and 4-pyridyl (6)], were synthesized. Here, we discuss a comparison of their molecular and crystal structures, with those of a related compound, 1‑bromo-2-(2-pyridyl)ferrocene (5). Although the crystal packings of 1–5 are classified into quasi-one-dimensional chain structures, their intermolecular interactions are different. Compounds 1–3 exhibit Br⋅⋅⋅cyclopentadienyl halogen bonds to form extended structures. In contrast, 4 shows the π–π stacking interactions between the pyrimidine rings of adjacent molecules, and 5 exhibits the Br⋅⋅⋅N halogen bonds between adjacent molecules. The crystal structures contained chiral molecules of opposing handedness.

Exploring the nonlinear optical properties of hypoxanthinium salts: a structural and computational analysis.

In this study, we detail the synthesis and crystallographic characterization of an unprecedented structure, specifically hypoxanthinium chloride monohydrate ((I) hereafter), which crystallizes in the monoclinic P21/c space group. A comparative analysis was conducted with four related hypoxanthinium salts: hypoxanthinium bromide monohydrate (II), 9-methylhypoxanthinium chloride monohydrate (III), hypoxanthinium nitrate monohydrate (IV), and hypoxanthinium perchlorate monohydrate (V). This analysis has focused mainly on their crystal packing, hydrogen-bonding networks, and non-classical intermolecular interactions, as elucidated by comprehensive Hirshfeld surface and topological analyses. Theoretical investigation of the nonlinear optical (NLO) properties of the hypoxanthinium derivatives (I-V) was performed using the Density Functional Theory (DFT). The crystalline environment was simulated using the iterative Supermolecule method (SM), and the static and dynamics linear refractive index, linear polarizability, second-order hyperpolarizability, and the third-order nonlinear susceptibility at the DFT/CAM-B3LYP/6-311++G(d,p) level were computed. The results for the macroscopic third-order nonlinear susceptibility of (II) was found to equal . By replacing the bromine atom in (II) with a chlorine atom as in (III), the value will be multiplied by 2.16, and therefore these results are large enough to suggest the potential application of these crystals as NLO materials.

Exploring the Explosive Potential: Synthesis and Characterization of Ring-Fused Oxadiazolo[3,4-b]pyrazine 1-Oxide Polymorphs with Balanced Energetic Properties.

A novel fused-ring compound, 5-azido-6-oxo-6,7-dihydro-[1,2,5]oxadiazolo[3,4-b]pyrazine 1-oxide (3a), was synthesized for the first time with simple two-step process and characterized using various spectroscopic techniques such NMR, IR, EA and HRMS. Two polymorphs (α-3a and β-3a) identified by SCXRD differ in crystal packing and noncovalent interactions, demonstrating high density, substantial heat of formation, and superior detonation properties with reduced mechanical sensitivity compared to TNT, TATB, and close to RDX, suggesting their potential as environmentally friendly high energy density materials.

Vapor pressure of tetrasubstituted metal phthalocyanines bearing fluorine substituents in non-peripheral positions

In this paper, the temperature dependence of the saturated vapor pressure of fluorosubstituted phthalocyanines with substituents in non-peripheral positions of the macroring, viz. MPcF4-np, M=Cu, Fe, Co, VO, was investigated by the Knudsen effusion method with mass spectrometric registration of the gaseous phase composition. The standard thermodynamic parameters [Formula: see text]°[Formula: see text] and [Formula: see text]°[Formula: see text] of the sublimation process of these compounds were determined. The results were compared with the vapor pressure of the corresponding MPcF4-p analogs bearing F-substituents in the peripheral positions. It was shown that the volatility decreased in the order of VOPcF4-np > CoPcF4-np ∼ CuPcF4-np ∼ FePcF4-np > ZnPcF4-np, which correlated with the increase in their crystal lattice energy in the same order. The volatility of most MPcF4-np (M = Cu, Zn, Co, VO) was lower than that of MPcF4-p. The results were analyzed from the point of view of crystal packing and intermolecular interactions in the crystal.

Crystal structure characterization, Hirshfeld surface analysis, and DFT calculation studies of 1-(6-amino-5-nitronaphthalen-2-yl)ethanone

The title compound, C12H10N2O3, was obtained by the deacetylation reaction of 1-(6-amino-5-nitronaphthalen-2-yl)ethanone in a concentrated sulfuric acid methanol solution. The molecule comprises a naphthalene ring system bearing an acetyl group (C-3), an amino group (C-7), and a nitro group (C-8). In the crystal, the molecules are assembled into a two-dimensional network by N...H/H...N and O...H/H...O hydrogen-bonding interactions. n–π and π–π stacking interactions are the dominant interactions in the three-dimensional crystal packing. Hirshfeld surface analysis indicates that the most important contributions are from O...H/H...O (34.9%), H...H (33.7%), and C...H/H...C (11.0%) contacts. The energies of the frontier molecular orbitals were computed using density functional theory (DFT) calculations at the B3LYP-D3BJ/def2-TZVP level of theory and the LUMO–HOMO energy gap of the molecule is 3.765 eV.

Synthesis and structural characterization of poly-thiolactones with varied ring sizes and endocyclic functional groups

The synthesis and isolation of new thiolactone species containing endocyclic ether, polyether, and lactone groups were designed using the reaction between diacyl chlorides with organometallic tin compounds as a template for controlled thioester bond formation. Thus, eight polythiolactones, including cyclo and spiro compounds with different ring sizes and functional groups were prepared, namely 1-oxa-4,9-dithiacycloundecane-5,8-dione (1a), 1-oxa-4,10-dithiacyclododecane-5,9-dione (1b), 1,4-dioxa-7,12-dithiacyclotetradecane-8,11-dione (2a), 1,4-dioxa-7,13-dithiacyclopentaecane-8,12-dione (2b), 2,15,19,32-tetraoxa-6,11,23,28-tetrathia-spiro[16.16]tritriacontane 3,7,10,14,20,24,27,31-octaone (3a), 2,16,20,34-tetraoxa-6,12,24,30-tetrathia-spiro[17.17]pentatriacontan-3,7,11,15,21,25,29,33-octaone (3b), 9,12,25,28-tetraoxa-6,15,22,31-tetratia-1(1,4),17(1,4)-diphenylcyclodotriacontane-5,16,21,32-tetraone (2c), and 2,17,21,36-tetraoxo-6,13,25,32-tetrathia-8(1,4)27(1,4)-diphenyl-spiro[18-18]heptatriacontane-3,7,12,16,22,26,31,35-octaone (3c). The structural characteristics of the eight closely related derivatives were determined by examining the impact of ring size and functional groups, through single-crystal X-ray diffraction techniques. The crystal packing of these polythiolactones was found to be mainly governed by weak C-H···O hydrogen bonding and van der Waals interactions, resulting in partially overlapping tubular arrangements. Hirshfeld analysis was performed to investigate the crystal packing and intermolecular interactions. The results of this study show the possibility of forming 3D tubular arrangements using polythiolactones with various endocyclic groups, including both flexible and rigid spacers.

Halogen Bonding as a Supramolecular Modulator of Crystal Packing and Exchange Interactions in Nitronyl Nitroxides

Halogen Bonding as a Supramolecular Modulator of Crystal Packing and Exchange Interactions in Nitronyl Nitroxides

Synthesis, crystal structure, exploration of the supramolecular assembly through Hirshfeld surface analysis of new 2,4-dihydro-1H-1,2,4-triazole-3-selones and 3,3′-di(4H-1,2,4-triazolyl)diselenides

The reaction of aromatic ring-substituted isoselenocyanates with 2-thiopheacetic and 4-pyridinecarboxylic acid hydrazides yielded selenosemicarbazides, which were further converted into previously unknown 1,2,4-triazole-3-selones and 3,3′-di(4H-1, 2,4-triazolyl)diselenides. The structure of the obtained compounds was studied by X-ray diffraction analysis and NMR spectroscopy. Theoretically, the reactivity and nonlinear optical (NLO) properties were predicted by using the DFT-B3LYP method. Charge separation and orbital analysis were performed by using the frontier molecular orbital (FMO) and natural population analysis (NPA). 5aa, 5ca, and 5ab show significantly reduced HOMO-LUMO gaps and ionization potential (IP) among the other compounds. The density of states (DOS) spectra was plotted to get a pictorial representation of orbital and their energies. The highest βo value of 1754.31 au is obtained for 7fb which is indicating its excellent NLO properties. Nature and strength of Intermolecular interactions in crystal packing is considered through Hirshfeld surface (HS) analysis using the CrystalExplorer. Hence, the studied compounds have significant reactivity and NLO properties and may open a new door in searching for new NLO materials.

A Hydrazone Derivative: Synthesis, Crystal Structure, Supramolecular Assembly Exploration by Hirshfeld Surface Analysis and Computational Study

The diazotization reaction of o-trifluoromethyl aniline from aromatic amines with 5,5-dimethylcyclohexane-1,3-dione was studied, as a result, 2-(2-(o-trifluoromethylphenyl)hydrazono)-5,5-dimethylcyclohexane-1 ,3-dione (THDCD) was synthesized and its structure was confirmed by X-ray diffraction analysis. The solid state assembly is stabilized by numerous intermolecular interactions which are deeply probed by Hirshfeld surface analysis. The enrichment ratio was computed for getting the contact with the highest propensity to form crystal packing interaction. The mechanical response of the crystal is predicted by voids analysis. Moreover, interaction energy calculations were performed at HF/3-21G electron density model to further inspect the supramolecular assembly of the crystal. DFT calculation was conducted using B3LYP level with 6–311++G(d, p) basic set with the help of Gaussian 09W and GaussView 6.0 packages. MEP surface, HOMO-LUMO orbitals, and NBO theory were analyzed via DFT approach. Theoretical method confirms the proposed geometry of THDCD by X-ray analysis.

Interfacial Water Molecules as Agents for Phase Change Control and Proton Conductivity Enhancement in the Ammonium Vanadyl Tartrate System.

This study demonstrates the reversible structural transformation, single-crystal-to-single-crystal, of the ammonium vanadyl (L-tartrate) complex salt from the hydrate phase to the anhydrous phase. The transformation can be initiated by stimuli, such as temperature, humidity, or vacuum conditions. The hydrate and anhydrous phases exhibit a tetragonal structure (P41212), with marked differences in hydrogen bonding due to the presence or absence of one water molecule per asymmetric unit. The intricate relationship between crystal packing and intermolecular interactions in the hydrate phase was investigated by crystallographic charge density analysis revealing, at the molecular level, the reasons for the observed 5 orders of magnitude higher proton conductivity of the hydrate phase compared to that of the anhydrous phase. To gain further insight into the processes occurring at the surfaces of grain boundaries and the proton transfer mechanisms in this system, rehydration of the complex salt was carried out by using D2O instead of H2O and monitored by in situ ATR-FTIR spectroscopy. The results highlight the critical role of interfacial water molecules in driving structural transformations and influencing proton conductivity.

Structural Elucidation, In vitro and In silico Biological Evaluations of New Fluorinated Chalcone Derivatives for Potential Antioxidant Activity

Abstract: The newly synthesized fluorinated chalcone derivatives are observed to possess antioxidant potential. Two new fluorinated chalcone compounds were effectively synthesized using the Claisen- Schmidt condensation reaction and were recrystallized using the slow evaporation method. The single crystal structure of the compounds was determined and refined through the X-ray single crystal diffraction method. All compounds were subjected to computational structural characterization and Hirshfeld surface analysis. The compounds were then further characterized through the Ultravioletvisible (UV-Vis) spectroscopic study. The chalcone derivatives were further analysed with biological experimentation and simulation such as in vitro antioxidant (DPPH) assay, molecular docking and in silico ADMET study. The crystal packing revealed that the molecules in the compounds were linked together through the intermolecular C—H···O and C—H···π interactions. Hirshfeld surface analysis validated the presence of intermolecular interactions in crystal packing. The UV-Vis spectroscopic study revealed that the absorption wavelength of the compounds that range from 421.79 to 428.98 nm was within the visible region with the energy gap value of 2.58 to 2.62 eV. The DPPH assay disclosed weak antioxidant activity of both compounds (-31 to 20 %, 10000 μg/mL) compared to the standard ascorbic acid (94.5 %, 50 μg/mL). The binding energy of the docked complex inside the target protein, 2CAG was within the range of -7.3 to -7.5 kcal/mol. In the silico model, SwissADME predicted that the two compounds have overall good drug-like properties. Different substituents, more planar configuration and high intramolecular interactions in the crystal packing played their role in increasing the antioxidant activities, binding energy and drug likeliness of the synthesized compounds.

Supramolecular Structure, Hirshfeld Surface Analysis, Morphological Study and DFT Calculations of the Triphenyltetrazolium Cobalt Thiocyanate Complex

Polymorphism is a prevalent occurrence in pharmaceutical solids and demands thorough investigation during product development. This paper delves into the crystal growth and structure of a newly synthesized polymorph (TPT)2[CoII(NCS)4], (1), where TPT is triphenyl tetrazolium. The study combines experimental and theoretical approaches to elucidate the 3D framework of the crystal structure, characterized by hydrogen-bonded interactions between (TPT)+ cations and [Co(NCS)4]2− anions. Hirshfeld surface analysis, along with associated two-dimensional fingerprints, is employed to comprehensively investigate and quantify intermolecular interactions within the structure. The enrichment ratio is calculated for non-covalent contacts, providing insight into their propensity to influence crystal packing interactions. Void analysis is conducted to predict the mechanical behavior of the compound. Utilizing Bravais-Friedel, Donnay-Harker (BFDH), and growth morphology (GM) techniques, the external morphology of (TPT)2[CoII(NCS)4] is predicted. Experimental observations align well with BFDH predictions, with slight deviations from the GM model. Quantum computational calculations of the synthesized compounds is performed in the ground state using the DFT/UB3LYP level of theory. These calculations assess the molecule’s stability and chemical reactivity, including the computation of the HOMO-LUMO energy difference and other chemical descriptors. The study provides a comprehensive exploration of the newly synthesized polymorph, shedding light on its crystal structure, intermolecular interactions, mechanical behavior, and external morphology, supported by both experimental and computational analyses.

Crystal Structure, Hirshfeld Surface Analysis, and Biological Activities of Schiff-Base Derivatives of 4-Aminoantipyrine.

Eight Schiff bases, synthesized by the reaction of 4-aminoantipyrine with different cinnamaldehydes, were studied in the solid state by using vibrational spectroscopy (IR) and X-ray diffraction techniques. The analysis was extended to the solution phase through ultraviolet-vis, fluorescence spectroscopy, and cyclic voltammetry. Finally, the crystal structures of four compounds (3b, 3d, 3g, and 3h) were determined and studied. In addition to the experimental study, theoretical calculations using the semiempirical method PM6/ZDO were performed to understand better the compound's molecular properties, UV-vis, and infrared spectra. The primary difference is the angular conformation of the terminal phenyl rings around the corresponding linking C-N and C-C σ-bonds. Furthermore, as a result of extended bonding, the > C=N- azomethine group-containing Cpyr-N=(CH)-(CR)=(CH)-Cbz chain (with R=H for 3b, 3d, and 3h, and R=CH3 for 3g) is planar, nearly coplanar, with the mean plane of the pyrazole ring. Hirshfeld surface (HS) analysis was used to investigate the crystal packing and intermolecular interactions, which revealed that intermolecular C-H···O and C-H···N hydrogen bonds, π···π stacking, and C-H···π and C=O···π interactions stabilize the compounds. The energy contributions to the lattice energies of potential hydrogen bonds were primarily dispersive and repulsive. All derivatives were tested in vitro on LPS-stimulated mouse macrophages to assess their ability to suppress the LPS-induced inflammatory responses. Only a slight reduction in the level of NO production was found in activated macrophages treated with 3h. Additionally, the derivatives were tested for antimicrobial activity against several clinical bacteria and fungi strains, including three biofilm-forming microorganisms. Nevertheless, only Schiff base 3f showed interesting antibacterial activities with minimum inhibitory concentration (MIC) values as low as 15.6 μM against Enterobacter gergoviae. On the other hand, Schiff base 3f and, to a lesser extent, 3b and 3h showed antifungal activity against clinical isolates of Candida. The lowest MIC value was for 3f against Candida albicans (15.6 μM). It is interesting to note that the same Schiff bases exhibit the highest activity in both biological evaluations.

Crystal Structure and Intermolecular Energy for Some Nandrolone Esters.

Nandrolone (Estr-4-en-17β-ol-3-one) is a derivative of testosterone and a naturally occurring anabolic-androgenic agent which belongs to the steroid group. Crystal structures of four short, medium and long esterified forms of nandrolone, including propionate, phenylpropionate, cypionate and undecanoate were determined using single-crystal X-ray diffraction. Crystal packing, supramolecular features and intermolecular interactions were described based on a quantitative and qualitative Hirshfeld surfaces analysis accompanied by evaluation of crystal energies and intermolecular interactions computation. Also, the solubility of the esters was investigated from a pharmaceutical perspective.

Forcing Twisted 1,7‐Dibromoperylene Diimides to Flatten in the Solid State: What a Difference an Atom Makes

AbstractPerylene diimides (PDI) are workhorses in the field of organic electronics, owing to their appealing n‐semiconducting properties. Optimization of their performances is widely pursued by bay‐atom substitution and diverse imide functionalization. Bulk solids and thin‐films of these species crystallize in a variety of stacking configurations, depending on the geometry of the stable conformation of the polyaromatic core. We here demonstrate that 1,7‐dibromo‐substituted perylene diimides, PDI(H2Br2), possessing a heavily twisted conformation in the gas phase, in solution and in the solids, can be easily flattened in the solid state into centrosymmetric molecules if the polyaromatic cores form π–π stabilized chains. This is achieved by using axial residues with low stereochemical hindrance, as guaranteed by a single CH2/NH spacer directly linked to the imide function. Structural powder diffraction and DFT calculations on four newly designed species of the PDI(H2Br2) class coherently show that, thanks to the flexibility of the N−X−Ar link (X=CH2/NH), flat cores are indeed obtained by overcoming the interconversion barrier between twisted atropoisomers, of only 26.5 kJ mol−1. This strategy may then be useful to induce “anomalously flat” polyaromatic cores of different kinds (substituted acenes/rylenes) in the solid state, towards suitable crystal packing and orbital interactions for improved electronic performances.

Forcing Twisted 1,7-Dibromoperylene Diimides to Flatten in the Solid State: What a Difference an Atom Makes.

Perylene diimides (PDI) are workhorses in the field of organic electronics, owing to their appealing n-semiconducting properties. Optimization of their performances is widely pursued by bay-atom substitution and diverse imide functionalization. Bulk solids and thin-films of these species crystallize in a variety of stacking configurations, depending on the geometry of the stable conformation of the polyaromatic core. We here demonstrate that 1,7-dibromo-substituted perylene diimides, PDI(H2 Br2 ), possessing a heavily twisted conformation in the gas phase, in solution and in the solids, can be easily flattened in the solid state into centrosymmetric molecules if the polyaromatic cores form π-π stabilized chains. This is achieved by using axial residues with low stereochemical hindrance, as guaranteed by a single CH2 /NH spacer directly linked to the imide function. Structural powder diffraction and DFT calculations on four newly designed species of the PDI(H2 Br2 ) class coherently show that, thanks to the flexibility of the N-X-Ar link (X=CH2 /NH), flat cores are indeed obtained by overcoming the interconversion barrier between twisted atropoisomers, of only 26.5 kJ mol-1 . This strategy may then be useful to induce "anomalously flat" polyaromatic cores of different kinds (substituted acenes/rylenes) in the solid state, towards suitable crystal packing and orbital interactions for improved electronic performances.

Activation Loop Plasticity and Active Site Coupling in the MAP Kinase, ERK2

Previous studies of the protein kinase, ERK2, using NMR and hydrogen-exchange measurements have shown changes in dynamics accompanying its activation by phosphorylation. However, knowledge about the conformational motions involved is incomplete. Here, we examined ERK2 using long conventional molecular dynamics (MD) simulations starting from crystal structures of phosphorylated (2P) and unphosphorylated (0P) forms. Individual trajectories were run for (5 to 25) μs, totaling 727 μs. The results show unexpected flexibility of the A-loop, with multiple long-lived (>5 μs) conformational states in both 2P- and 0P-ERK2. Differential contact network and principal component analyses reveal coupling between the A-loop fold and active site dynamics, with evidence for conformational selection in the kinase core of 2P-ERK2 but not 0P-ERK2. Simulations of 2P-ERK2 show A-loop states corresponding to restrained dynamics within the N-lobe, including regions around catalytic residues. One A-loop conformer forms lasting interactions with the L16 segment, leading to reduced RMSF and greater compaction in the active site. By contrast, simulations of 0P-ERK2 reveal excursions of A-loop residues away from the C-lobe, leading to greater active site mobility. Thus, the A-loop in ERK2 switches between distinct conformations that reflect coupling with the active site, possibly via the L16 segment. Crystal packing interactions suggest that lattice contacts with the A-loop may restrain its structural variation in X-ray structures of ERK2. The novel conformational states identified by MD expand our understanding of ERK2 regulation, by linking the activated state of the kinase to reduced dynamics and greater compaction surrounding the catalytic site.