SUMO: In Silico Sequence Assessment Using Multiple Optimization Parameters.

To select the most promising screening hits from antibody and VHH display campaigns for subsequent in-depth profiling and optimization, it is highly desirable to assess and select sequences on properties beyond only their binding signals from the sorting process. In addition, developability risk criteria, sequence diversity, and the anticipated complexity for sequence optimization are relevant attributes for hit selection and optimization. Here, we describe an approach for the in silico developability assessment of antibody and VHH sequences. This method not only allows for ranking and filtering multiple sequences with regard to their predicted developability properties and diversity, but also visualizes relevant sequence and structural features of potentially problematic regions and thereby provides rationales and starting points for multi-parameter sequence optimization.

On the mechanism of intermolecular nitrogen-atom transfer from a lattice-isolated diruthenium nitride intermediate.

Catalyst confinement within microporous media provides the opportunity to site isolate reactive intermediates, enforce intermolecular functionalization chemistry by co-localizing reactive intermediates and substrates in molecular-scale interstices, and harness non-covalent host-guest interactions to achieve selectivities that are complementary to those accessible in solution. As part of an ongoing program to develop synthetically useful nitrogen-atom transfer (NAT) catalysts, we have demonstrated intermolecular benzylic amination of toluene at a Ru2 nitride intermediate confined within the interstices of a Ru2-based metal-organic framework (MOF), Ru3(btc)2X3 (btc = 1,3,5-benzenetricarboxylate, i.e., Ru-HKUST-1 for X = Cl). Nitride confinement within the extended MOF lattice enabled intermolecular C-H functionalization of benzylic C-H bonds in preference to nitride dimerization, which was encountered with soluble molecular analogues. Detailed study of the kinetic isotope effects (KIEs, i.e., kH/kD) of C-H amination, assayed both as intramolecular effects using partially labeled toluene and as intermolecular effects using a mixture of per-labeled and unlabeled toluene, provided evidence for restricted substrate mobility on the time scale of interstitial NAT. Analysis of these KIEs as a function of material mesoporosity provided approximate experimental values for functionalization in the absence of mass transport barriers. Here, we disclose a combined experimental and computational investigation of the mechanism of NAT from a Ru2 nitride to the C-H bond of toluene. Computed kinetic isotope effects for a H-atom abstraction (HAA)/radical rebound (RR) mechanism are in good agreement with experimental data obtained for C-H amination at the rapid diffusion limit. These results provide the first detailed analysis of the mechanism of intermolecular NAT to a C-H bond, bolster the use of KIEs as a probe of confinement effects on NAT within MOF lattices, and provide mechanistic insights unavailable by experiment because rate-determining mass transport obscured the underlying chemical kinetics.

Computational Mechanistic Study of Electro-Oxidation of Ammonia to N2 by Homogenous Ruthenium and Iron Complexes.

A comprehensive DFT study of the electrocatalytic oxidation of ammonia to dinitrogen by a ruthenium polypyridyl complex, [(tpy)(bpy)RuII(NH3)]2+ (a), and its NMe2-substituted derivative (b) is presented. The thermodynamics and kinetics of electron (ET) and proton transfer (PT) steps and transition states are calculated. NMe2 substitution on bpy reduces the ET steps on average 8 kcal/mol for complex b as compared to a. The calculations indicate that N-N formation occurs by ammonia nucleophilic attack/H-transfer via a nitrene intermediate rather than a nitride intermediate. Comparison of the free energy profiles of Ru-b with its first-row Fe congener reveals that the thermodynamics are less favorable for the Fe-b model, especially for ET steps. The N-H bond dissociation free energies (BDFEs) for NH3 to form N2 show the following trend: Ru-b < Ru-a < Fe-b, indicating the lowest and most favorable BDFEs for Ru-b complex.

Effect of Appended S-Block Metal Ion Crown Ethers on Redox Properties and Catalytic Activity of Mn-Nitride Schiff Base Complexes: Methane Activation.

Using density functional theory (DFT), the effects of appended s-block metal ion crown ethers upon the redox properties of the following nitridomanganese(V) salen complexes were investigated: [(salen)MnV(N)(Mn+-crown ether)]n+ (salen = N,N'-bis(salicydene)ethylenediamine; M = Na+, K+, Ba2+, and Sr2+ for 1Na, 1K, 1Ba, and 1Sr, respectively; A = complex without Mn+-crown ether and B = without Mn+). NBO analysis of the MnN bond orders, optimized bond lengths, and stretching frequencies changes upon oxidation for all species show that for A, B, and 1Na MnN has more nitridyl character while a nitride form is more significant for 1K, 1Ba, and 1Sr. The results reveal that ΔGrxn(e-) and thus E1/2 are quite sensitive to the point charge (q) of the s-block metal ions (1 for K+/Na+ and 2 for Ba2+/Sr2+). Computations suggest that the degree of delocalization of the HOMO electrons on the supporting ligand is modified by the chelated s-block metal ion. Methane activation by A•+, 1K•+, and 1Ba•+ complexes proceeds via a hydrogen atom transfer (HAT) pathway with reasonable barriers for all complexes with ∼4 kcal/mol difference in energy. The molecular electrostatic potential (MEP) maps indicate a shift in redox potential imposed by the nonredox active cations by altering the electrostatic potential of the complexes. Computations show that the complexes with higher point charge of the incorporated metal ions result in higher N-H bond BDFEs. Changes in predicted properties as a function of continuum solvent dielectric constant suggest that the primary effect of the appended s-block ion is via "through space" interactions.

Methane C-H Activation via 3d Metal Methoxide Complexes with Potentially Redox-Noninnocent Pincer Ligands: A Density Functional Theory Study.

This paper reports a density functional theory study of 3d transition-metal methoxide complexes with potentially redox-noninnocent pincer supporting ligands for methane C-H bond activation to form methanol (LnM-OMe + CH4 → LnM-Me + CH3OH). The three types of tridentate pincer ligands [terpyridine (NNN), bis(2-pyridyl)phenyl-C,N,N' (NCN), and 2,6-bis(2-phenyl)pyridine-N,C,C' (CNC)] and different first-row transition metals (M = Ti, V, Cr, Mn, Fe, Co, Ni, and Cu) are used to elucidate the reaction mechanism as well as the effect of the metal identity on the thermodynamics and kinetics of a methane activation reaction. Spin-density analysis indicates that some of these systems, the NNN and NCN ligands, have redox-noninnocent character. A four-centered, kite-shaped transition state, σ-bond metathesis, or oxidative hydrogen migration has been found for methane activation for the complexes studied. Calculations suggest that the d electron count is a more significant factor than the metal formal charge in controlling the thermodynamics and kinetics of C-H activation and late 3d metal methoxides, with high d counts preferred. Notably, early-to-middle metals tend toward oxidative hydrogen migration and late metals undergo a pathway that is more akin to σ-bond metathesis, suggesting that metal methoxide complexes that favor σ-bond metathesis pathways for methane activation will yield lower barriers for C-H activation.