Benchmarking ANI potentials as a rescoring function and screening FDA drugs for SARS-CoV-2 Mpro.

Here, we introduce the use of ANI-ML potentials as a rescoring function in the host-guest interaction in molecular docking. Our results show that the "docking power" of ANI potentials can compete with the current scoring functions at the same level of computational cost. Benchmarking studies on CASF-2016 dataset showed that ANI is ranked in the top 5 scoring functions among the other 34 tested. In particular, the ANI predicted interaction energies when used in conjunction with GOLD-PLP scoring function can boost the top ranked solution to be the closest to the x-ray structure. Rapid and accurate calculation of interaction energies between ligand and protein also enables screening of millions of drug candidates/docking poses. Using a unique protocol in which docking by GOLD-PLP, rescoring by ANI-ML potentials and extensive MD simulations along with end state free energy methods are combined, we have screened FDA approved drugs against the SARS-CoV-2 main protease (Mpro). The top six drug molecules suggested by the consensus of these free energy methods have already been in clinical trials or proposed as potential drug molecules in previous theoretical and experimental studies, approving the validity and the power of accuracy in our screening method.

Computational analysis of substrate recognition of Sars-Cov-2 Mpro main protease.

Mpro main protease takes an essential role in the Sars-Cov-2 viral life cycle by releasing the individual protein from the single poly-peptide chain via proteolytic cleavage in the beginning of the viral infection. Interfering with this step by inhibiting the protease with small compound-based inhibitors has been proven to be an effective strategy to treat the infection. Thus, understanding the substrate recognition mechanism of the Mpro main protease has gained great interest from the beginning of the pandemic. Here, we have studied the substrate recognition mechanism of the protease by means of the molecular dynamic methods. We have found that the glutamine residue at P1 has paramount effect in the interaction with the substrates as expected. In addition, we also have shown that for the first time, the arginine amino acid at the P3-P5 along with P4' can strengthen the interaction.

Exploring potential Plasmodium kinase inhibitors: a combined docking, MD and QSAR studies.

Malaria is a disease caused mostly by Plasmodium falciparum, affects millions of people each year. The kinases are validated targets for malaria infection. In this study, we investigate for real and hypothetical compounds that can inhibit cyclic guanosine monophosphate (CGMP)-dependent protein kinase using molecular docking via combined similarity analysis, molecular dynamics simulations, quantitative structure activity relationship (QSAR). Using Tanimoto similarity scores, ∼8.4 million compounds were screened. Compounds that have at least 70% similarity are used in further analysis. These compounds are assessed by means of docking, MMBPSA, MMGBSA and ANI_LIE. Based on consensus of different free energy methods and docking we revealed two potential inhibitors that can be useful for treatment of malaria. Apart from screening of real compounds, we have also selected the 10 most plausible hypothetical compounds by performing QSAR. By QSAR proposed pharmacophores, we generated over 247 hypothetical compounds and among them 19 molecules with lower QSAR predicted IC50 values and high docking scores were selected for further analysis. We selected the top 10 inhibitor candidates and performed MD simulations for free energy calculations like the protocol applied for real compounds. According to the free energy calculations, we suggest 2 real (C34H29F5N8O4S and C30H27F2N7O2S2, PubChem IDs: 140564801 and 89035196, respectively) and 2 hypothetical (C23H27FN6O2S, MOL3 and C23H25FN6O2S, MOL4) compounds that can be effective inhibitors against the protein kinase of Plasmodium falciparum.Communicated by Ramaswamy H. Sarma.

Exploring epigenetic drugs as potential inhibitors of SARS-CoV-2 main protease: a docking and MD simulation study.

The COVID-19 pandemic has caused havoc around the globe since 2019 and is considered the largest global epidemic of the twentieth century. Although the first antiviral drug, Remdesivir, was initially introduced against COVID­19, virtually no tangible therapeutic drugs exist to treat SARS-CoV-2 infection. FDA-approved Paxlovid (Nirmatrelvir supplemented by Ritonavir) was recently announced as a promising drug against the SARS-CoV-2 major protease (Mpro). Here we report for the first time the remarkable inhibitory potentials of lead epigenetic-targeting drugs (epi-drugs) against SARS-CoV-2 Mpro. Epi-drugs are promising compounds to be used in combination with cancer chemotherapeutics to regulate gene expression. The search for all known epi-drugs for the specific inhibition of SARS-CoV-2 Mpro was performed for the first time by consensus (three high-order program) molecular docking studies and end-state free energy calculations. Several epi-drugs were identified with highly comparable binding affinity to SARS-CoV-2 Mpro compared to Nirmatrelvir. In particular, potent histone methyltransferase inhibitor EPZ005687 and DNA methyltransferase inhibitor Guadecitabine were prominent as the most promising epi-drug inhibitors for SARS-CoV-2 Mpro. Long Molecular dynamics (MD) simulations (200 ns each) and corresponding MM-GBSA calculations confirmed the stability of the EPZ005687-Mpro complex with MM-GBSA binding free energy (ΔGbind) -48.2 kcal/mol (EPZ005687) compared to Nirmatrelvir (-44.7 kcal/mol). Taken together, the antiviral activities of the highlighted epi-drugs are reported beyond widespread use in combination with anti-cancer agents. The current findings therefore highlight as yet unexplored antiviral potential of epi-drugs suitable for use in patients struggling with chronic immunosuppressive disorders.Communicated by Ramaswamy H. Sarma.

Revisiting MMPBSA by Adoption of MC-Based Surface Area/Volume, ANI-ML Potentials, and Two-Valued Interior Dielectric Constant.

Here, we report the accuracy improvements of molecular mechanics Poisson-Boltzmann surface area (MMPBSA) calculations by adoption of ANI-ML potentials in replacement of MM terms, the use of solvent-accessible surface area (SASA) and volume (SAV) values from the Monte Carlo sampling of the probe, and introducing two different interior dielectric constants for electrostatic interactions of protein-ligand (P-L) and polar solvation term in the MMPBSA calculations. Our results show that the Pearson correlation coefficients of MMPBSA-calculated values with respect to experimental binding free energies can be drastically improved from 0.48 to 0.90 by adoption of ANI-ML potentials in replacement of MM energy terms in the equation, referred to as ANI-PBSA. Moreover, we show that the SASA/SAV-combined equation in the scaled particle theory (SPT) can be a better choice to model nonpolar solvation term, reaching nearly the same accuracy by ANI-PBSA calculations. Finally, we introduce two different values of interior dielectric constants, which could be an alternative strategy between the single and variable constant definitions.

The performance of ANI-ML potentials for ligand-n(H2 O) interaction energies and estimation of hydration free energies from end-point MD simulations.

Here, we investigate the performance of "Accurate NeurAl networK engINe for Molecular Energies" (ANI), trained on small organic compounds, on bulk systems including non-covalent interactions and applicability to estimate solvation (hydration) free energies using the interaction between the ligand and explicit solvent (water) from single-step MD simulations. The method is adopted from ANI using the Atomic Simulation Environment (ASE) and predicts the non-covalent interaction energies at the accuracy of wb97x/6-31G(d) level by a simple linear scaling for the conformations sampled by molecular dynamics (MD) simulations of ligand-n(H2 O) systems. For the first time, we test ANI potentials' abilities to reproduce solvation free energies using linear interaction energy (LIE) formulism by modifying the original LIE equation. Our results on ~250 different complexes show that the method can be accurate and have a correlation of R2  = 0.88-0.89 (MAE <1.0 kcal/mol) to the experimental solvation free energies, outperforming current end-state methods. Moreover, it is competitive to other conventional free energy methods such as FEP and BAR with 15-20 × fold reduced computational cost.

Accurate Binding Free Energy Method from End-State MD Simulations.

Herein, we introduce a new strategy to estimate binding free energies using end-state molecular dynamics simulation trajectories. The method is adopted from linear interaction energy (LIE) and ANI-2x neural network potentials (machine learning) for the atomic simulation environment (ASE). It predicts the single-point interaction energies between ligand-protein and ligand-solvent pairs at the accuracy of the wb97x/6-31G* level for the conformational space that is sampled by molecular dynamics (MD) simulations. Our results on 54 protein-ligand complexes show that the method can be accurate and have a correlation of R = 0.87-0.88 to the experimental binding free energies, outperforming current end-state methods with reduced computational cost. The method also allows us to compare BFEs of ligands with different scaffolds. The code is available free of charge (documentation and test files) at https://github.com/otayfuroglu/deepQM.

A neural network potential for the IRMOF series and its application for thermal and mechanical behaviors.

Metal-organic frameworks (MOFs) with their exceptional porous and organized structures have been the subject of numerous applications. Predicting the bulk properties from atomistic simulations requires the most accurate force fields, which is still a major problem due to MOFs' hybrid structures governed by covalent, ionic and dispersion forces. Application of ab initio molecular dynamics to such large periodic systems is thus beyond the current computational power. Therefore, alternative strategies must be developed to reduce computational cost without losing reliability. In this work, we construct a generic neural network potential (NNP) for the isoreticular metal-organic framework (IRMOF) series trained by PBE-D4/def2-TZVP reference data of MOF fragments. We confirmed the success of the resulting NNP on both fragments and bulk MOF structures by prediction of properties such as equilibrium lattice constants, phonon density of states and linker orientation. The RMSE values of energy and force for the fragments are only 0.0017 eV atom-1 and 0.15 eV Å-1, respectively. The NNP predicted equilibrium lattice constants of bulk structures, even though not included in training, are off by only 0.2-2.4% from experimental results. Moreover, our fragment based NNP successfully predicts the phenylene ring torsional energy barrier, equilibrium bond distances and vibrational density of states of bulk MOFs. Furthermore, the NNP enables revealing the odd behaviors of selected MOFs such as the dual thermal expansion properties and the effect of mechanical strain on the adsorption of hydrogen and methane molecules. The NNP based molecular dynamics (MD) simulations suggest IRMOF-4 and IRMOF-7 to have positive-to-negative thermal expansion coefficients while the rest to have only negative thermal expansion at the studied temperatures of 200 K to 400 K. The deformation of the bulk structure by reduction of the unit cell volume has been shown to increase the volumetric methane uptake in IRMOF-1 but decrease the volumetric methane uptake in IRMOF-7 due to the steric hindrance. To the best of our knowledge, this study presents the first pre-trained model publicly available giving the opportunity for the researchers in the field to investigate different aspects of IRMOFs by performing large-scale simulation at the first-principles level of accuracy.

Molecular dynamics simulations reveal the plausible agonism/antagonism mechanism by steroids on androgen receptor mutations.

Androgen receptors (AR) are the primary drug target in prostate cancer (PCa). There are several drugs developed against its activity for prostate cancer treatment, but cancer cells revive AR signaling against those drugs by using alternative steroids such as glucocorticoids. In addition, antagonists become agonists due to emergence of mutations in AR gene. The mechanism by which antagonists are converted into agonists and how AR signaling is recovered by other steroids has yet to be fully elucidated. In this study, we interrogated the role of bicalutamide conformation in its antagonist function and how glucocorticoids such as prednisolone and dexamethasone revive AR signaling at the molecular level by means of molecular dynamics. We found that the ''closed'' conformation of bicalutamide is essential for its antagonist function and W741 residue is forcing it into this conformation. Moreover, we show that prednisolone and dexamethasone behave like natural agonist DHT which confirm the experimental results that show their role in the reviving AR signaling in the case of ARL701H mutation.

Experimental and theoretical investigation of water-soluble silicon(IV) phthalocyanine and its interaction with bovine serum albumin.

Photodynamic therapy (PDT) has drawn a great scientific attention to cancer treatment over the last decades. However, the bottleneck for the PDT is to find good photosensitizers (PSs) with greater water solubility, no aggregation, and fast discharge from the body. Therefore, there are still a big scientific desire for the synthesizing new rational PSs for treatment of cancer by PDT technique. In favor of improving the competence of PDT, an axially bis[4-(diphenylamino-1,1'-biphenyl-4-ol)] substituted silicon(IV) phthalocyanine (3) was converted to its water-soluble quaternized derivative (3Q). Their structures were fully characterized by single-crystal X-ray diffraction, elemental analysis, and different spectroscopic methods such as FT-IR, UV-Vis, MALDI-TOF, and 1H-NMR. The photophysical properties such as fluorescence quantum yields and lifetimes, and the photochemical properties such as singlet oxygen generation of both phthalocyanines were investigated. Ground and excited-state calculations were performed to explain the observed electronic absorption spectra. The addition of the 4-diphenylamino-1,1'-biphenyl-4-ol groups on the axially positions of the silicon(IV) phthalocyanine increased the singlet oxygen quantum yield from 0.15 to around 0.20. Especially quaternized compound 3Q showed high singlet oxygen quantum yield of 0.26 in water solution. In addition, a spectroscopic investigation of the binding behavior of the quaternized silicon (IV) phthalocyanine complex to bovine serum albumin (BSA) is also studied in this work, confirming the possible interaction. Further theoretical calculations were carried out to find out the plausible-binding regions of the BSA protein. Axially bis[4-(diphenylamino-1,1'-biphenyl-4-ol)] substituted silicon(IV) phthalocyanine (3) was converted to its quaternized water soluble derivative (3Q). The photophysical properties such as fluorescence quantum yields and lifetimes, and the photochemical properties such as singlet oxygen generation of both phthalocyanines were investigated. In addition, a spectroscopic investigation of the binding behavior of the quaternized silicon (IV) phthalocyanine complex to bovine serum albumin (BSA) is also studied in this work, confirming the possible interaction. Further theoretical calculations were carried out to find out the plausible binding regions of the BSA protein.

Rotational Thromboelastometry Profile in Children With Chronic Spontaneous Urticaria.

The pathogenesis of chronic spontaneous urticaria (CSU) is incompletely understood. There is a growing interest in the role of the coagulation cascade in chronic urticaria. Rotational thromboelastometry (ROTEM) assay enables the global assessment of coagulation status. In the present study, we aimed to test the coagulation profile in children with CSU using ROTEM and correlate these parameters with those of a healthy group. A total of 24 children with active CSU (11 girls and 13 boys) 8 to 17 years of age and age-matched and sex-matched 30 healthy control participants were enrolled in the study. ROTEM assays (intrinsic thromboelastometry and extrinsic thromboelastometry) were used to measure and analyze coagulation time, clot formation time, and maximum clot firmness. The CSU patients and controls did not differ in age, sex, erythrocyte, neutrophil, and platelet counts. Also, ROTEM parameters did not show any difference between the 2 groups. ROTEM is increasingly being used as a tool for monitoring coagulation status. In this study, ROTEM parameters did not show any difference between CSU patients and the healthy group. Further studies are needed to confirm our findings on a larger number of CSU patients.

In Silico Investigation into H2 Uptake in MOFs: Combined Text/Data Mining and Structural Calculations.

Metal-organic frameworks (MOFs) with high surface areas and adjustable lattice structures are attractive for gas storage and thus have been a great interest in research. Although tremendous amount of data on MOFs have been available in the literature, there are very few studies considering methodological approach for H2 uptake properties of MOFs. In this study, we systematically investigated the H2 uptake capabilities of MOFs by means of text and data mining (TDM) through retrieving data of the surface areas (SA) and pore volumes (PV) from published manuscripts. In addition, we calculated theoretical SA and PV values of all real MOFs available in Cambridge Structural Database (CSD). Prior to calculation, we applied an automated structure analysis algorithm that loads the coordinates of molecules from CSD experimental X-ray single-crystal structure and removes guest/solvent contaminants from the structure. We compared SA, PV, and H2 uptake data from both TDM and structural calculation techniques and unraveled a list of MOFs with H2 uptakes predicted from both experimental and theoretical SA/PV values that may be regarded as the most promising candidates for H2 storage. The extensive and systematic TDM strategy estimates 5975 experimental SA and 7748 experimental PV values (2080 MOFs with SA + PV values) with 78-82% success rate. In addition, structural calculations reveal the theoretical SA and PV values along with a theoretical H2 adsorption limit of MOFs in the absence of guest molecules. Combination of both TDM and structural calculation strategies provides a more comprehensive perspective for the investigation of hydrogen storage capacities in MOFs, which elucidates plausibility of new compounds as candidates for H2 storage materials.

HBGA binding modes and selectivity in noroviruses upon mutation: a docking and molecular dynamics study.

Norovirus, also called winter vomiting bug, is the most common cause for gastroenteritis and severe childhood diarrhea disease. High mutation rates cause drug resistance and thus complicate the development of an effective therapeutics against virus infection. The virus protein enters the host cell via the interaction with histo-blood group antigens (HBGAs), formed by oligosaccharides. To date, the crystal structures of numerous complexes of virus proteins with different antigens have been reported. The HBGAs bind to the two distinct regions of the virus proteins. Herein, the affinity of different variants of virus protein to some common glycans has been computationally analyzed. Molecular docking studies as combination of docking scores and rmsd values revealed that the binding region 1 is more attractive for the ligands in variants of categories 1-5, but selectivity is drastically shifted to region 2 due to in category 6. In addition, molecular dynamics simulations were unraveled when the region 1 is hindered (in category 6); the blocking loop has less fluctuation than that of unblocked in other categories.

Molecular Dynamics Studies of Histo-Blood Group Antigen Blocking Human Immunoglobulin A Antibody and Escape Mechanism in Noroviruses Upon Mutation.

Norovirus is the causing agent of acute gastroenteritis disease globally. Efforts in developing therapeutics against virus infection mostly fail due to emergence of drug resistance that is a consequence of presence of high mutation rates in virus genome during virus' life cycle. In this study, we computationally analyzed the affinity of a drug target, wild type VP1 envelope protein and its three variants to a therapeutic antibody FAB5I2. We have found that mutations break important hydrogen bonds and cause high fluctuations in residues that form VP1-FAB5I2 complex interface. In addition to changes in dynamics, we also revealed that the affinity of FAB5I2 to VP1 protein drops significantly upon mutations in terms of relative binding free energy.

Thromboelastogram as a Tool to Predict Hypercoagulability in Children With Cystic Fibrosis.

Increased thrombophilic tendency in patients with cystic fibrosis (CF) has recently been reported. The determinants of thrombosis in children with CF remain largely unknown. Our aim in this study was to evaluate the thromboelastography (TEG) profile of children with CF through ROTEM (whole blood rotation thromboelastometry). Nineteen patients with CF and 20 controls were included in the study. Whole blood count, prothrombin time, activated prothrombin time, fibrinogen, d-dimer levels, and ROTEM assays (INTEM, EXTEM) were performed. Clotting time, clot formation time (CFT), and maximum clot firmness (MCF) were determined by INTEM and EXTEM analysis. In INTEM assay, MCF ( P = .001) value was significantly increased and CFT ( P = .031) value was decreased in patients with CF compared with those of the control group. In the EXTEM assay, there was a similar significant increase in MCF ( P = .023) value in patients with CF compared with that of the control group. There was a significant positive correlation between fibrinogen levels and MCF in EXTEM ( r = .72) and INTEM ( r = .76) assays, whereas there was a negative correlation with CFT in EXTEM ( r = -.61) and INTEM ( r = -.67). The results of our study indicated that TEG profiles in patients with CF were more hypercoagulable compared with those of the control group.

Docking, molecular dynamics and free energy studies on aspartoacylase mutations involved in Canavan disease.

The disruption of aspartoacylase enzyme's catalytic activity causes fatal neurodegenerative Canavan disease. By molecular dynamics and docking methods, here we studied two deleterious mutations that have been identified in the Canavan patients' genotype E285A, F295S, and revealed the possible cause for the enzyme inhibition due to the drastic changes in active site dynamics, loss of interactions among Arg 71, Arg 168 and the substrate and pKa value of critical Glu178 residue. In addition to changes in the enzyme dynamics, free energy calculations show that the binding energy of substrate decreases dramatically up on mutations.

Presence of a single nucleotide polymorphism (RS3758581) in a boy with DRESS syndrome.

Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is a rare, potentially life-threatening, drug-induced hypersensitivity reaction that includes rash, hematologic abnormalities, lymphadenopathy, and internal organ involvement. The pathogenesis of DRESS syndrome is partially understood. Various medications have been described as the cause of DRESS syndrome. Phenytoin and allopurinol are the most commonly reported culprit drugs, although more than 50 drugs can induce DRESS syndrome. Members of the cytochrome P450 (CYP) superfamily are the most commonly involved enzymes in metabolism of drugs such as phenytoin. This case report addresses the influence of CYP2C9 genetic polymorphism (a single nucleotide polymorphism) on phenytoin drug metabolism, thereby causing DRESS syndrome.

Computational insights into the protonation states of catalytic dyad in BACE1-acyl guanidine based inhibitor complex.

Developing small compound based drugs targeting the ß-secretase (BACE) enzyme is one of the most promising strategies in treatment of the Alzheimer's disease. As the enzyme shows the activity based on the acid-base reaction at a very narrow pH range, the protonation state of aspartic acids with the residue number 32 and 228 (Asp32 and Asp228), which forms the active site dyad, along with the protonation state of the ligand (substrate or inhibitor) play very critical role in interactions between the ligand and enzyme. Thus, understanding the nature of the protonation state of both enzyme's active site dyad and ligand is crucial for drug design in Alzheimer's disease field. Here we have investigated the protonation state of the Asp32 and Asp228 residues in the presence of a highly potent beta secretase inhibitor, containing acyl guanidine warhead that have recently been devised but not extensively studied. Our Quantum Mechanical, Molecular Dynamics and Docking studies on all the possible protonation states have suggested that the dyad residues are in di-deprotonated states in the presence of protonated inhibitor.

Health-care conditions in elementary schools and teachers' knowledge of childhood asthma.

BACKGROUND: For the adequate control of asthma in school-age children, it is recommended that teachers, school health personnel and administrators should have sufficient knowledge of how to manage asthma during school hours. AIM: To investigate asthma health care in elementary schools, and teachers' knowledge of childhood asthma and its management. METHODS: The extent of knowledge of childhood asthma in 2779 teachers in 141 elementary schools (children aged 6-14, grades 1-8) in Bursa, the fourth largest city in Turkey, was evaluated. Section I comprised questions about asthma health-care in schools, Section II teachers' knowledge of the main characteristics of asthma and Section III (Likert Scale) teachers' detailed knowledge of the signs, triggering factors, treatment and general knowledge of asthma. RESULTS: The findings of Section I demonstrated that the organisation of health-care for asthma in schools was insufficient. Of the teachers questioned, 14·7% were not even aware and only 1% and 9·6% of the teachers had been made aware by school health personnel and school records, respectively, of asthmatic children. Only 27·3% of the teachers stated that they were responsible for the health of an asthmatic child. The majority of teachers (70%) said that asthmatic children could use the medication (e.g. inhalers) themselves. In Section II, there were between 44·1% and 75·5% correct answers, while in Section III this figure ranged from 3·3% to 78·4%. The correct answer rate was 60·4% for Sections II and III combined. The results of Sections II and III showed that the teachers' knowledge of asthma was poor in many respects. Teachers who stated that they had asthma or had first-degree relatives with asthma, or those with 10 or more years' experience provided significantly more correct answers in Sections II and III combined than did those without these characteristics (P<0·001). CONCLUSIONS: There is a need to improve and standardise health care for asthma (asthma management policies) in schools. The implementation of asthma education programmes for teachers and other staff responsible for pupils' health should result in better control of this common disease.

Vibrational Spectroscopy Reveals Varying Structural Motifs in Cu(+)(CH4)(n) and Ag(+)(CH4)(n) (n = 1-6).

Vibrational spectra are measured for Cu(+)(CH4)(Ar)2, Cu(+)(CH4)2(Ar), Cu(+)(CH4)n (n = 3-6), and Ag(+)(CH4)n (n = 1-6) in the C-H stretching region (2500-3100 cm(-1)) using photofragment spectroscopy. Spectra are obtained by monitoring loss of Ar or CH4. Interaction with the metal ion produces substantial red shifts in the C-H stretches of proximate hydrogens. The magnitude of the shift reflects the metal-methane distance and the coordination to the metal ion of the methane hydrogens (η(2) or η(3)). The structures of the complexes are determined by comparing the measured spectra with spectra calculated for candidate geometries using the B3LYP and CAM-B3LYP density functionals with 6-311++G(3df,3pd) and aug-cc-pVTZ-PP basis sets. Because of the d(10) electronic configuration of the metal ions, the complexes are expected to adopt symmetric structures, which is confirmed by the experiments. All of the complexes have η(2) hydrogen coordination in the first shell, in accord with theoretical predictions; second-shell ligands sometimes show η(3) hydrogen coordination. The vibrational spectrum of Cu(+)(CH4)(Ar)2 shows extensive structure due to Fermi resonance between the lowest-frequency C-H stretch and overtones of the H-C-H bends. The Cu(+)(CH4) cluster has a smaller red shift in the lowest-frequency C-H stretch than M(+)(CH4), M(+) = Co(+) (d(8)) and Ni(+) (d(9)). Although all three ions have similar binding energies, the metal-ligand electrostatic interaction is largest for Cu(+), while the contribution from covalent interactions is largest for Co(+). The larger ionic radius of Ag(+) leads to a larger metal-ligand distance and weaker interaction, resulting in substantially smaller red shifts than in the Cu(+) complexes. The Cu(+)(CH4)2 and Ag(+)(CH4)2 clusters have symmetrical structures, with the methanes on opposite sides of the metal, while Cu(+)(CH4)3 and Ag(+)(CH4)3 adopt symmetrical, trigonal planar structures with all M-C distances equal. For Cu(+)(CH4)4, the tetrahedral structure dominates the observed spectrum, although a trigonal pyramidal structure may contribute; however, only the tetrahedral structure is observed for Ag(+)(CH4)4. The structures of Cu(+)(CH4)n and Ag(+)(CH4)n differ for clusters with n > 4. For copper complexes, these are primarily formed by adding outer-shell methane ligand(s) to the tetrahedral n = 4 core. The observed spectra of the larger Ag(+) clusters are dominated by symmetrical structures in which all of the Ag-C distances are similar: Ag(+)(CH4)5 has a trigonal bipyramidal geometry and Ag(+)(CH4)6 is octahedral.