Excessive MYC-topoisome activity triggers acute DNA damage, MYC degradation, and replacement by a p53-topoisome.

Hyperproliferation driven by the protooncogene MYC may lead to tumor suppressor p53 activating DNA damage that has been presumed to derive from hypertranscription and over-replication. Here, we report that excessive MYC-topoisome (MYC/topoisomerase 1/topoisomerase 2) activity acutely damages DNA-activating pATM and p53. In turn, MYC is shut off and degraded, releasing TOP1 and TOP2A from MYC topoisomes in vitro and in vivo.

SARS-CoV-2 spike fusion peptide interaction with phosphatidylserine lipid triggers membrane fusion for viral entry.

Unlabelled: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike is the fusion machine for host cell entry. Still, the mechanism by which spike protein interacts with the target lipid membrane to facilitate membrane fusion during entry is not fully understood. Here, using steady-state membrane fusion and single-molecule fluorescence resonance energy transfer imaging of spike trimers on the surface of SARS-CoV-2 pseudovirion, we directly show that spike protein interacts with phosphatidylserine (PS) lipid in the target membrane for mediating fusion.

Proposed dual membrane contact with full-length Osh4.

Membrane contacts sites (MCSs) play important roles in lipid trafficking across cellular compartments and maintain the widespread structural diversity of organelles. We have utilized microsecond long all-atom (AA) molecular dynamics (MD) simulations and enhanced sampling techniques to unravel the MCS structure targeting by yeast oxysterol binding protein (Osh4) in an environment that mimics the interface of membranes with an increased proportion of anionic lipids using CHARMM36m forcefield with additional CUFIX parameters for lipid-protein electrostatic interactions. In a dual-membrane environment, unbiased MD simulations show that Osh4 briefly interacts with both membranes, before aligning itself with a single membrane, adopting a β-crease-bound conformation similar to observations in a single-membrane scenario.

Modeling the membrane binding mechanism of a lipid transport protein Osh4 to single membranes.

All-atom (AA) molecular dynamics simulations are used to unravel the binding mechanism of yeast oxysterol binding protein (Osh4) to model membranes with varying anionic lipid concentration using AA and the highly mobile membrane mimetic (HMMM) representations. For certain protein-lipid interactions, an improved forcefield description is used (CUFIX) to accurately describe lipid-protein electrostatic interactions. Our detailed computational studies have identified a single, β-crease oriented, membrane-bound conformation of Osh4 for all anionic membranes.

External electric field control: driving the reactivity of metal-free azide-alkyne click reactions.

Recent reports have suggested that an external electric field (EEF) can assist and even control product selectivity. In this work, we have shown that the barrier for the Huisgen reaction between alkyl (aryl) azide and cyclooctyne(biflurocyclooctyne) is reduced by ∼3-4 kcal mol when an oriented EEF is applied along the reaction axis. As a consequence of their inherently polar transition-states (TSs), a parallel orientation of the EEF results in enhancement of the charge transfer (CT) between the fragments and concomitant increase in the dipole moment along the reaction axes.

Understanding the Reactivity of CO and NO Radicals toward S-Containing and Aromatic Amino Acids.

The reactivity of CO and NO radicals toward six amino acid side chains namely, cysteine (Cys), methionine (Met), phenylalanine (Phe), tyrosine (Tyr), histidine (His), and tryptophan (Trp), has been explored using state-of-art density functional theory (DFT) and transition state theory (TST). Three reaction mechanisms, namely hydrogen atom abstraction (HAT), radical adduct formation (RAF), and single electron transfer (SET), have been considered for detailed study. While CO radical is highly reactive toward majority of amino acids, the reactivity of NO radical is limited.

Tunneling Control: Competition between 6π-Electrocyclization and [1,5]H-Sigmatropic Shift Reactions in Tetrahydro-1H-cyclobuta[e]indene Derivatives.

Direct dynamics calculation using canonical variational transtition state theory (CVT) inclusive of small curvature tunneling (SCT) reveals the influential role of quantum mechanical tunneling (QMT) for 2,2a,5,7b-tetrahydro-1H-cyclobuta[e]indene derivatives (2a-2j) in governing their product selectivity. 2a-2j follow two distinct reaction channels, namely, 6π-electrocyclization (2 → 3) and [1,5]H-sigmatropic shift (2 → 4), among which the activation barrier is higher for [1,5]H-shift (2 → 4), thereby favoring the kinetically controlled product (3a-3j) as anticipated. However, SCT calculations show that a narrower barrier and smaller mass of participating atoms make QMT more pronounced for [1,5]H-shift reaction despite its higher activation energy, which results in a competition between kinetic controlled (2 → 3) and tunneling controlled (2 → 4) products.

Strain Control: Reversible H2 Activation and H2/D2 Exchange in Pt Complexes.

Experiments have indicated that bulky ligands are required for efficient H2 activation by Pt-Sn complexes. Herein, we unravel the mechanisms for a Pt-Sn complex, Pt(Sn(t)Bu3)2(CN(t)Bu)2 (1a), catalyzed reversible H2 activation. Among a number of Pt-Sn catalysts used to model H2 activation and H2/D2 exchange reactions, only 1a with large strain was found to be suitable because the addition of H2 to 1a requires lowest distortion energy, minimal structural changes, and smallest entropy of activation.

Role of Heavy Atom Tunneling in Myers-Saito Cyclization of Cyclic Enyne-Cumulene Systems.

Direct dynamics calculation using canonical variational transtition state theory (CVT) inclusive of small curvature tunneling (SCT) reveals heavy atom tunneling in Myers-Saito cyclization of 10- and 9-membered cyclic enyne-cumulene systems like 1,6-didehydro[10]annulene and derivative of neocarzinostatin, respectively. The pure density functional theory functional, BLYP at a 6-31+G (d,p) basis set reproduce the observed reaction energies and barriers within 1.0 kcal/mol.

Metal Free Azide-Alkyne Click Reaction: Role of Substituents and Heavy Atom Tunneling.

Metal free click reactions provide an excellent noninvasive tool to modify and understand the processes in biological systems. Release of ring strain in cyclooctynes on reaction with azides on the formation of triazoles results in small activation energies for various intermolecular Huisgen reactions (1-9). Substitution of difluoro groups at the α, α' position of the cyclooctyne ring enhances the rates of cycloadditions by 10 and 20 times for methyl azide and benzyl azide respectively at room temperature.

Understanding the mechanisms of unusually fast H-H, C-H, and C-C bond reductive eliminations from gold(III) complexes.

Carbon-carbon bond reductive elimination from gold(III) complexes are known to be very slow and require high temperatures. Recently, Toste and co-workers have demonstrated extremely rapid CC reductive elimination from cis-[AuPPh3 (4-F-C6 H4 )2 Cl] even at low temperatures. We have performed DFT calculations to understand the mechanistic pathway for these novel reductive elimination reactions.

Tunneling assists the 1,2-hydrogen shift in N-heterocyclic carbenes.

At room temperature, 1,2-hydrogen-transfer reactions of N-heterocyclic carbenes, like the imidazol-2-ylidene to give imidazole is shown to occurr almost entirely (>90 %) by quantum mechanical tunneling (QMT). At 60 K in an Ar matrix, for the 2, 3-dihydrothiazol-2-ylidene→thiazole transformation, QMT is shown to increase the rate about 10(5)  times. Calculations including small-curvature tunneling show that the barrier for intermolecular 1,2-hydrogen-transfer reaction is small, and QMT leads to a reduced rate of the forward reaction because of nonclassical reflections even at room temperature.

Role of quantum mechanical tunneling on the γ-effect of silicon on carbenes in 3-trimethylsilylcyclobutylidene.

Quantum mechanical tunneling (QMT) is increasingly being realized as an important phenomenon that can enhance the rate of reactions even at room temperature. Recently, the ability of a trimethylsilane (TMS) group to activate 1,3-H shift to a carbene from a γ-position has been demonstrated. Direct dynamical calculations (using canonical varitational transition state theory) inclusive of small curvature tunneling (CVT-SCT) show that QMT plays a decisive role in such 1,3-hydrogen migration in both the presence and absence of TMS.