Experiences with an Inquiry-Based Ionic Liquid Module in an Undergraduate Physical Chemistry Laboratory.

The topic of ionic liquids is typically not taught at the undergraduate level. Many properties, such as conductivity, vapor pressure, and viscosity, of these so-called "green solvents" are unique compared to traditional molecular solvents. Using active learning techniques, we introduced an ionic liquid module in the physical chemistry laboratory where their structures and physical properties, namely, viscosity, conductivity, and vapor pressure, were explored in relation to molecular solvents. Summative and formative assessments show that a majority of the participants were able to grasp the key concepts of ionic liquids. We envision that our methods and strategies can be one of the building blocks of introducing ionic liquids into the undergraduate chemistry curriculum.

Hydrogen-Bonded Complexes in Binary Mixture of Imidazolium-Based Ionic Liquids with Organic Solvents.

Though local structures in ionic liquids are dominated by strong Coulomb forces, directional hydrogen bonds can also influence the physicochemical properties of imidazolium-based ionic liquids. In particular, the C-2 position of the imidazolium cation is acidic and can bind with suitable hydrogen bond acceptor sites of molecular solvents dissolved in imidazolium-based ionic liquids. In this report, we identify hydrogen-bonded microenvironments of the model ionic liquid, 1-ethyl-3-methylimidazolium tris(pentafluoroethyl) trifluorophosphate, and the changes that occur when molecular solvents are dissolved in it by using a C-D infrared reporter at the C-2 position of the cation. Our linear and nonlinear infrared experiments, along with computational studies, indicate that the molecular solvent dimethyl sulfoxide can form strong hydrogen-bonded dimers with the cation of the ionic liquid at the C-2 position. In contrast, acetone, which is also a hydrogen bond acceptor similar to dimethyl sulfoxide, does not show evidence of cation-solvent hydrogen-bonded conformers at the C-2 position. The outcome of our study on a broad scale strengthens the importance of cation-solute interactions in ionic liquids.

Role of Integrative Oncology and Palliative Care Services in Improving Comfort Level and Compliance among Patients with Advanced Fungating Breast Cancer - Experience from a Rural Hospital of North Eastern India during the COVID-19 Pandemic.

Objectives: Malignant fungating breast cancers are a definite challenge to treatment due to limited knowledge and prevailing distressing symptoms. Various treatment protocols with regard to radiotherapy (RT) and chemotherapy have been reported in the literature but the knowledge of proper integration of these regimes with effective palliative care nursing care, particularly in resource poor settings, is not well understood. Hence, this study was undertaken to assess the change in the degree of comfort achieved before and after treatment of these fungating breast cancer wounds along with issues regarding compliance to such treatment in a peripheral rural medical college hospital. Materials and Methods: A total of 20 patients were selected from the medical records files of the RT department of North Bengal Medical College and Hospital who were registered and treated during the period 1 June 2019- 31 July 2021. Palliative care nursing of malodour, bleeding, maggots, pain and assessment of psychological parameters was done based on the 11-point revised Edmonton Symptom Assessment Scale at the beginning and at each subsequent follow-up visits. Patients were also individualised for receiving palliative RT, chemotherapy, surgery and hormone therapy based on their clinicodemographic profiles. Informed consent was taken from all patients and every treatment was in accordance with the ethical permissions as sought from the Institutional Ethics Committee. Statistical analysis was done based on descriptive statistics and SPSS version 22. Results: Median follow-up was 13 months. Overall, there was a significant improvement in comfort and well-being as assessed by paired t-test before and after treatment (paired t-test = 16.548; P = 0.000). However, there was no significant correlation with palliative radiation dose and schedule as per spearman's correlation coefficient. The mean radiation dose was BED 48.56 Gy3 (EQD2 = 29.3 Gy3) and the median number of fractions used was 10. Almost 50% of patients were noncompliant to treatment and this might be attributed to the prevailing COVID-19 pandemic situation. There was maximum relief with regard to bleeding control (100%), malodour dissipation (76.9%) and control of maggots infestation (71%) and these results were also found to be strongly associated with treatment as per analysis done by Chi-square test of difference of proportions. Conclusion: Effective comfort can be achieved with proper judicious combination of palliative care nursing and other oncological treatment such as radiation, chemotherapy and surgery.

Calcium-dependent titin-thin filament interactions in muscle: observations and theory.

Gaps in our understanding of muscle mechanics demonstrate that the current model is incomplete. Increasingly, it appears that a role for titin in active muscle contraction might help to fill these gaps. While such a role for titin is increasingly accepted, the underlying molecular mechanisms remain unclear. The goals of this paper are to review recent studies demonstrating Ca2+-dependent interactions between N2A titin and actin in vitro, to explore theoretical predictions of muscle behavior based on this interaction, and to review experimental data related to the predictions. In a recent study, we demonstrated that Ca2+ increases the association constant between N2A titin and F-actin; that Ca2+ increases rupture forces between N2A titin and F-actin; and that Ca2+ and N2A titin reduce sliding velocity of F-actin and reconstituted thin filaments in motility assays. Preliminary data support a role for Ig83, but other Ig domains in the N2A region may also be involved. Two mechanical consequences are inescapable if N2A titin binds to thin filaments in active muscle sarcomeres: (1) the length of titin's freely extensible I-band should decrease upon muscle activation; and (2) binding between N2A titin and thin filaments should increase titin stiffness in active muscle. Experimental observations demonstrate that these properties characterize wild type muscles, but not muscles from mdm mice with a small deletion in N2A titin, including part of Ig83. Given the new in vitro evidence for Ca2+-dependent binding between N2A titin and actin, it is time for skepticism to give way to further investigation.

C-D Vibration at C2 Position of Imidazolium Cation as a Probe of the Ionic Liquid Microenvironment.

Unlike molecular solvents, imidazolium-based ionic liquids are entirely made of ions with spatial heterogeneity. There is a need for spectroscopic probes that can assess the microenvironment near the cations of these complex liquids. In this manuscript, we describe simple chemical procedures to label the C2 position of imidazolium cation with a C-D vibrational probe and show, through linear and nonlinear vibrational spectroscopies, that this C-D stretching mode can be a useful analytical tool to assess both the solvent microenvironment and solute-solvent interactions in imidazolium-based ionic liquids from the cation point of view. It is expected that this C-D vibration probe on the cation will lead to the development of innovative experimental strategies that can provide a better understanding of such ionic liquids.

Calcium increases titin N2A binding to F-actin and regulated thin filaments.

Mutations in titin are responsible for many cardiac and muscle diseases, yet the underlying mechanisms remain largely unexplained. Numerous studies have established roles for titin in muscle function, and Ca2+-dependent interactions between titin and actin have been suggested to play a role in muscle contraction. The present study used co-sedimentation assays, dynamic force spectroscopy (DFS), and in vitro motility (IVM) assays to determine whether the N2A region of titin, overlooked in previous studies, interacts with actin in the presence of Ca2+. Co-sedimentation demonstrated that N2A - F-actin binding increases with increasing protein and Ca2+ concentration, DFS demonstrated increased rupture forces and decreased koff in the presence of Ca2+, and IVM demonstrated a Ca2+-dependent reduction in motility of F-actin and reconstituted thin filaments in the presence of N2A. These results indicate that Ca2+ increases the strength and stability of N2A - actin interactions, supporting the hypothesis that titin plays a regulatory role in muscle contraction. The results further support a model in which N2A - actin binding in active muscle increases titin stiffness, and that impairment of this mechanism contributes to the phenotype in muscular dystrophy with myositis. Future studies are required to determine whether titin - actin binding occurs in skeletal muscle sarcomeres in vivo.

Analysis of single, cisplatin-induced DNA bends by atomic force microscopy and simulations.

Bent DNA, or DNA that is locally more flexible, is a recognition motif for many DNA binding proteins. These DNA conformational properties can thus influence many cellular processes, such as replication, transcription, and DNA repair. The importance of these DNA conformational properties is juxtaposed to the experimental difficulty to accurately determine small bends, locally more flexible DNA, or a combination of both (bends with increased flexibility). In essence, many current bulk methods use average quantities, such as the average end-to-end distance, to extract DNA conformational properties; they cannot access the additional information that is contained in the end-to-end distance distributions. We developed a method that exploits this additional information to determine DNA conformational parameters. The method is based on matching end-to-end distance distributions obtained experimentally by atomic force microscopy imaging to distributions obtained from simulations. We applied this method to investigate cisplatin GG biadducts. We found that cisplatin induces a bend angle of 36° and softens the DNA locally around the bend.

Ultrafast dynamics of ionic liquids in colloidal dispersion.

Ionic liquid (IL)-surfactant complexes have significance both in applications and fundamental research, but their underlying dynamics are not well understood. We apply polarization-controlled two-dimensional infrared spectroscopy (2D-IR) to study the dynamics of [BMIM][SCN]/surfactant/solvent model systems. We examine the effect of the choice of surfactants and solvent, and the IL-to-surfactant ratio (W-value), with a detailed analysis of the orientation and structural dynamics of each system. Different surfactants create very different environments for the entrapped ILs, ranging from a semi-static micro-environment to a fluxional environment that evolves even faster than the bulk IL. The oil-phase also clearly affects the microscopic dynamics. The anisotropy decay for entrapped ILs completes within 10 ps, which is similar to free thiocyanate ion in water, while a significant reorientation-induced spectral diffusion (RISD) effect is observed. The entrapped ionic liquid are highly dynamic for all W-values, and no core-shell structure is observed. We hypothesize that, instead of an ionic liquid-reverse micelle (IL-RM), the microscopic structure of this system is small colloidal dispersions or pairs of IL and surfactants. A detailed analysis of the polarization-controlled 2D-IR spectra of AOT system reveals a potential ion-exchange mechanism.

Synthesis, in vitro evaluation and molecular docking studies of novel amide linked triazolyl glycoconjugates as new inhibitors of α-glucosidase.

A series of N-substituted amide linked triazolyl ß-d-glucopyranoside derivatives (4a-l) were synthesized and their in vitro inhibitory activity against yeast α-glucosidase enzyme [EC.3.2.1.20] was assessed. Compounds 4e (IC50=156.06µM), 4f (IC50=147.94µM), 4k (IC50=127.71µM) and 4l (IC50=121.33µM) were identified as the most potent inhibitors for α-glucosidase as compared to acarbose (IC50=130.98µM) under the same in vitro experimental conditions. Kinetic study showed that both 4e and 4f inhibit the enzyme in a competitive manner with p-nitrophenyl α-d-glucopyranoside as substrate. Molecular docking studies of 4e, 4f, 4k and 4l were also carried out using homology model of α-glucosidase to find out the binding modes responsible for the inhibitory activity. This study revealed that the binding affinity of compounds 4e, 4f, 4k and 4l for α-glucosidase were -8.2, -8.6, -8.3 and -8.5kcal/mol respectively, compared to that of acarbose (-8.9kcal/mol). The results suggest that the N-substituted amide linked triazole glycoconjugates can reasonably mimic the substrates for the yeast α-glucosidase.

Single-Molecule Force Spectroscopy Studies of APOBEC3A-Single-Stranded DNA Complexes.

APOBEC3A (A3A) inhibits the replication of a range of viruses and transposons and might also play a role in carcinogenesis. It is a single-domain deaminase enzyme that interacts with single-stranded DNA (ssDNA) and converts cytidines to uridines within specific trinucleotide contexts. Although there is abundant information that describes the potential biological activities of A3A, the interplay between binding ssDNA and sequence-specific deaminase activity remains controversial. Using a single-molecule atomic force microscopy spectroscopy approach developed by Shlyakhtenko et al. [(2015) Sci. Rep. 5, 15648], we determine the stability of A3A in complex with different ssDNA sequences. We found that the strength of the complex is sequence-dependent, with more stable complexes formed with deaminase-specific sequences. A correlation between the deaminase activity of A3A and the complex strength was identified. The ssDNA binding properties of A3A and those for A3G are also compared and discussed.

Probing of miniPEGγ-PNA-DNA Hybrid Duplex Stability with AFM Force Spectroscopy.

Peptide nucleic acids (PNA) are synthetic polymers, the neutral peptide backbone of which provides elevated stability to PNA-PNA and PNA-DNA hybrid duplexes. It was demonstrated that incorporation of diethylene glycol (miniPEG) at the γ position of the peptide backbone increased the thermal stability of the hybrid duplexes (Sahu, B. et al. J. Org. Chem. 2011, 76, 5614-5627). Here, we applied atomic force microscopy (AFM) based single molecule force spectroscopy and dynamic force spectroscopy (DFS) to test the strength and stability of the hybrid 10 bp duplex. This hybrid duplex consisted of miniPEGγ-PNA and DNA of the same length (γ(MP)PNA-DNA), which we compared to a DNA duplex with a homologous sequence. AFM force spectroscopy data obtained at the same conditions showed that the γ(MP)PNA-DNA hybrid is more stable than the DNA counterpart, 65 ± 15 pN vs 47 ± 15 pN, respectively. The DFS measurements performed in a range of pulling speeds analyzed in the framework of the Bell-Evans approach yielded a dissociation constant, koff ≈ 0.030 ± 0.01 s⁻¹ for γ(MP)PNA-DNA hybrid duplex vs 0.375 ± 0.18 s⁻¹ for the DNA-DNA duplex suggesting that the hybrid duplex is much more stable. Correlating the high affinity of γ(MP)PNA-DNA to slow dissociation kinetics is consistent with prior bulk characterization by surface plasmon resonance. Given the growing interest in γ(MP)PNA as well as other synthetic DNA analogues, the use of single molecule experiments along with computational analysis of force spectroscopy data will provide direct characterization of various modifications as well as higher order structures such as triplexes and quadruplexes.

Near-Optimal Controller for Nonlinear Continuous-Time Systems With Unknown Dynamics Using Policy Iteration.

This paper presents a single-network adaptive critic-based controller for continuous-time systems with unknown dynamics in a policy iteration (PI) framework. It is assumed that the unknown dynamics can be estimated using the Takagi-Sugeno-Kang fuzzy model with arbitrary precision. The successful implementation of a PI scheme depends on the effective learning of critic network parameters. Network parameters must stabilize the system in each iteration in addition to approximating the critic and the cost. It is found that the critic updates according to the Hamilton-Jacobi-Bellman formulation sometimes lead to the instability of the closed-loop systems. In the proposed work, a novel critic network parameter update scheme is adopted, which not only approximates the critic at current iteration but also provides feasible solutions that keep the policy stable in the next step of training by combining a Lyapunov-based linear matrix inequalities approach with PI. The critic modeling technique presented here is the first of its kind to address this issue. Though multiple literature exists discussing the convergence of PI, however, to the best of our knowledge, there exists no literature, which focuses on the effect of critic network parameters on the convergence. Computational complexity in the proposed algorithm is reduced to the order of (Fz)(n-1) , where n is the fuzzy state dimensionality and Fz is the number of fuzzy zones in the states space. A genetic algorithm toolbox of MATLAB is used for searching stable parameters while minimizing the training error. The proposed algorithm also provides a way to solve for the initial stable control policy in the PI scheme. The algorithm is validated through real-time experiment on a commercial robotic manipulator. Results show that the algorithm successfully finds stable critic network parameters in real time for a highly nonlinear system.

APOBEC3G Interacts with ssDNA by Two Modes: AFM Studies.

APOBEC3G (A3G) protein has antiviral activity against HIV and other pathogenic retroviruses. A3G has two domains: a catalytic C-terminal domain (CTD) that deaminates cytidine, and a N-terminal domain (NTD) that binds to ssDNA. Although abundant information exists about the biological activities of A3G protein, the interplay between sequence specific deaminase activity and A3G binding to ssDNA remains controversial. We used the topographic imaging and force spectroscopy modalities of Atomic Force Spectroscopy (AFM) to characterize the interaction of A3G protein with deaminase specific and nonspecific ssDNA substrates. AFM imaging demonstrated that A3G has elevated affinity for deaminase specific ssDNA than for nonspecific ssDNA. AFM force spectroscopy revealed two distinct binding modes by which A3G interacts with ssDNA. One mode requires sequence specificity, as demonstrated by stronger and more stable complexes with deaminase specific ssDNA than with nonspecific ssDNA. Overall these observations enforce prior studies suggesting that both domains of A3G contribute to the sequence specific binding of ssDNA.

Two-dimensional ultrafast vibrational spectroscopy of azides in ionic liquids reveals solute-specific solvation.

The stereochemistry and the reaction rates of bimolecular nucleophilic substitution reactions involving azides in ionic liquids are governed by solute-solvent interactions. Two-dimensional ultrafast vibrational spectroscopy (2D-IR) shows that the picosecond dynamics of inorganic azides are substantially slower than organic azides in a series of homologous imidazolium ionic liquids. In water, both organic and inorganic azides spectrally diffuse with a ∼2 ps time constant. In the aprotic solvent tetrahydrofuran, both kinds of azides spectrally diffuse on a timescale >5 ps. In ionic liquids, like 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4]), organic azides spectrally diffuse with a 2-4 ps time constant, and inorganic azides spectrally diffuse with a >40 ps time constant. Such a striking difference suggests that neutral (organic) and charged (inorganic) azides are incorporated in the ionic liquids with different solvation structures.

Ultrafast vibrational spectroscopy (2D-IR) of CO2 in ionic liquids: Carbon capture from carbon dioxide's point of view.

The CO2ν3 asymmetric stretching mode is established as a vibrational chromophore for ultrafast two-dimensional infrared (2D-IR) spectroscopic studies of local structure and dynamics in ionic liquids, which are of interest for carbon capture applications. CO2 is dissolved in a series of 1-butyl-3-methylimidazolium-based ionic liquids ([C4C1im][X], where [X](-) is the anion from the series hexafluorophosphate (PF6 (-)), tetrafluoroborate (BF4 (-)), bis-(trifluoromethyl)sulfonylimide (Tf2N(-)), triflate (TfO(-)), trifluoroacetate (TFA(-)), dicyanamide (DCA(-)), and thiocyanate (SCN(-))). In the ionic liquids studied, the ν3 center frequency is sensitive to the local solvation environment and reports on the timescales for local structural relaxation. Density functional theory calculations predict charge transfer from the anion to the CO2 and from CO2 to the cation. The charge transfer drives geometrical distortion of CO2, which in turn changes the ν3 frequency. The observed structural relaxation timescales vary by up to an order of magnitude between ionic liquids. Shoulders in the 2D-IR spectra arise from anharmonic coupling of the ν2 and ν3 normal modes of CO2. Thermal fluctuations in the ν2 population stochastically modulate the ν3 frequency and generate dynamic cross-peaks. These timescales are attributed to the breakup of ion cages that create a well-defined local environment for CO2. The results suggest that the picosecond dynamics of CO2 are gated by local diffusion of anions and cations.

Thiocyanate as a local probe of ultrafast structure and dynamics in imidazolium-based ionic liquids: water-induced heterogeneity and cation-induced ion pairing.

Ultrafast two-dimensional infrared spectroscopy (2D-IR) of thiocyanate ([SCN]−) in 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([C4C1im][NTf2]) and 1-butyl-2,3-dimethylimidazolium bis(trifluoromethylsulfonyl)imide ([C4C1C1(2)im][NTf2]) ionic liquids probes local structure and dynamics as a function of the water content, solute counterion, and solute concentration. The 2D-IR spectra of the water-saturated ionic liquids resolve two distinct kinds of dynamics. This dynamical heterogeneity is explained as two subensembles, one with and one without a water molecule in the first solvation shell. When the countercation is K+, ion pairs between K+ and [SCN]− that persist for >100 ps are detected by long-lasting vibrational frequency correlations. The observed dynamics are invariant to [SCN]− concentration, which indicates that the [SCN]− does not cluster in ionic liquid solution. Taken together, these results are consistent with a picture of thiocyanate as a local probe that can interrogate ultrafast structure and dynamics at a small spatial scale in ionic liquids.

Hemi body irradiation: An economical way of palliation of pain in bone metastasis in advanced cancer.

BACKGROUND: The primary aim of this prospective non-randomized study was to evaluate the effect of hemi-body irradiation (HBI) on pain and quality of life in cancer patients with extensive bone metastases. The secondary aim was to evaluate side-effects and cost-effectiveness of the treatment. MATERIALS AND METHODS: Between March 2008 and December 2010, a total of 23 (male = 14, female = 9, median age = 60 years) diagnosed cases of metastatic cancer patients (prostate = 11, breast = 6, and lung = 6) received HBI, which was delivered as lower (n = 7) (dose = 8 Gy), upper (n = 8) (dose = 6 Gy), or sequential HBI (n = 8) with a Telecobalt unit (Theratron 780C). Among them, one lung cancer patient died at 2 months and one prostate cancer patient defaulted after the second follow-up. Thus, 21 patients (male = 13, female = 8, median age = 65 years) (prostatic cancer = 10, breast cancer = 6, and lung cancer = 5) were followed up for a minimum of 6 months. Evaluations were performed before and at 2, 4, 8, 16, and 24 weeks after treatment. Pain evaluation was done by Visual Analogue Scale (VAS), Verbal Rating Scale (VRS), Percentage of Pain Relief (PRR), and Global Pain Score (GPS). Toxicity was assessed by CTC v-3 toxicity scores in the medical record. Assessment of oral morphine consumption was done before and after radiation using paired t-test, and correlation analysis was also done with decrease of morphine consumption and reduction of pain score using statistical analysis. RESULTS: Response (control of pain) was partial (PR) in 67% and complete (CR) in 22% of patients. For most patients, the pain control lasted throughout the follow-up period (6 months). From 66.66% patients requiring 13 or more Morphine (10 mg) tablets per day prior to HBI, none of the patients required to consume 13 or more Morphine (10 mg) tablets per day following HBI, which was correlated with significant reduction in various pain scores (P < 0.05). One way ANOVA with Dunnett's Multiple Comparison Test (P < 0.05) was significant in VAS score changes, VRS score changes, PPR score changes, and GPS score changes. Along with the decrease in morphine tablets, the Linear Correlation of various scales for pain reduction like VAS, VRS, PPR, and GPS were significant. As such, the quality of life was better due to decreased pain and also, a decrease in the dose of analgesics. Grade 1 and 2 hematological toxicity and grade 1 diarrhea were observed as common side-effects. The average total cost of treatment including hospital stay, medicines, and radiation charges was around INR 400.00. CONCLUSION: This study shows that hemibody irradiation is not only an effective modality for palliation of severe bone pain in advanced cancer cases but also economical, involves short hospital stay, with acceptable side-effects, utilizes the simple Telecobalt machine, and is less cumbersome in comparison to other currently available pain palliation methods like oral morphine and radiopharmaceuticals.

Evaluation of Socio-demographic Factors for Non-compliance to Treatment in Locally Advanced Cases of Cancer Cervix in a Rural Medical College Hospital in India.

INTRODUCTION: Carcinoma cervix is a leading cause of cancer in India. However, majority of the patients face a problem of not being able to complete the treatment. AIM: This study was an attempt to find out the important causes of this non-compliance to treatment in a rural Medical College Hospital where majority of the cancer cases are of cervical cancer. RESULTS: Out of 144 patients studied over 2 years 88 cases could not complete the treatment. The study revealed that due old age 58.33% cases were defaulters, having many children at home meant a burden to 76.92% cases and 63.89% cases had a problem of not been able to travel a far distance of more than 100 km from home to hospital for treatment. CONCLUSION: These were the important factors of non-compliance and suggested more important than the issues of literacy and poor socio-economic status.

PROBING αIIbß3: LIGAND INTERACTIONS BY DYNAMIC FORCE SPECTROSCOPY AND SURFACE PLASMON RESONANCE.

The interaction between platelet integrin αIIbß3 and fibrin(ogen) plays a key role in blood clot formation and stability. Integrin antagonists, a class of pharmaceuticals used to prevent and treat cardiovascular disease, are designed to competitively interfere with this process. However, the energetics of the integrin-drug binding are not fully understood, potentially hampering further development of this class of pharmaceuticals. We integrated dynamic force spectroscopy (DFS) and surface plasmon resonance (SPR) to probe the energetics of complex formation between αIIbß3 and cHarGD, a cyclic peptide integrin antagonist. Analysis of αIIbß3:cHarGD DFS rupture force data at pulling rates of 14 000 pN/s, 42 000 pN/s and 70 000 pN/s yielded koff = 0.02-0.09 s-1, a dissociation energy barrier [Formula: see text] = 22-29 kJ/mol, and a potential well width x-1 = 0.5-0.8 nm. SPR kinetic data yielded an association rate constant kon = 7 × 103 L/mol-s and a dissociation rate constant koff = 10-2 s-1, followed by a slower stabilization step (τ ~ 400 s). Both DFS and SPR detected minimal interactions between αIIbß3 and cHarGA demonstrating a key role for electrostatic interactions between the ligand aspartate and the integrin metal ion-dependent adhesion site (MIDAS). Our work provides new insights into the energy landscape of αIIbß3's interactions with pharmacological and physiological ligands.