Integrating molecular dynamics simulation with small- and wide-angle X-ray scattering to unravel the flexibility, antigen-blocking, and protease-restoring functions in a hindrance-based pro-antibody.

Spatial hindrance-based pro-antibodies (pro-Abs) are engineered antibodies to reduce monoclonal antibodies' (mAbs) on-target toxicity using universal designed blocking segments that mask mAb antigen-binding sites through spatial hindrance. By linking through protease substrates and linkers, these blocking segments can be removed site-specifically. Although many types of blocking segments have been developed, such as coiled-coil and hinge-based Ab locks, the molecular structure of the pro-Ab, particularly the region showing how the blocking fragment blocks the mAb, has not been elucidated by X-ray crystallography or cryo-EM.

Structural insights into Nirmatrelvir (PF-07321332)-3C-like SARS-CoV-2 protease complexation: a ligand Gaussian accelerated molecular dynamics study.

Coronavirus 3C-like protease (3CLpro) is found in SARS-CoV-2 virus, which causes COVID-19. 3CLpro controls virus replication and is a major target for target-based antiviral discovery. As reported by Pfizer, Nirmatrelvir (PF-07321332) is a competitive protein inhibitor and a clinical candidate for orally delivered medication.

A universal in silico V(D)J recombination strategy for developing humanized monoclonal antibodies.

Background: Humanization of mouse monoclonal antibodies (mAbs) is crucial for reducing their immunogenicity in humans. However, humanized mAbs often lose their binding affinities. Therefore, an in silico humanization method that can prevent the loss of the binding affinity of mAbs is needed.

Correction: Development of a structure-based computational simulation to optimize the blocking efficacy of pro-antibodies.

[This corrects the article DOI: 10.1039/D1SC01748A.].

Development of a structure-based computational simulation to optimize the blocking efficacy of pro-antibodies.

The on-target toxicity of monoclonal antibodies (Abs) is mainly due to the fact that Abs cannot distinguish target antigens (Ags) expressed in disease regions from those in normal tissues during systemic administration. In order to overcome this issue, we "copied" an autologous Ab hinge as an "Ab lock" and "pasted" it on the binding site of the Ab by connecting a protease substrate and linker in between to generate a pro-Ab, which can be specifically activated in the disease region to enhance Ab selectivity and reduce side effects. Previously, we reported that 70% of pro-Abs can achieve more than 100-fold blocking ability compared to the parental Abs.

In silico studies of conformational dynamics of Mu opioid receptor performed using gaussian accelerated molecular dynamics.

G-protein-coupled receptors play a crucial role in various signaling pathways and function as targets for treating a wide spectrum of diseases. Since the twentieth century, extensive research has been conducted on the Mu opioid receptor (MOR) as a drug target. We examined the MOR inactivation and activation processes using an enhanced sampling method (Gaussian accelerated molecular dynamics), the binding pocket site area method, the root mean square deviation method, and the free energy (potential of mean force) method.

A fragment-based docking simulation for investigating peptide-protein bindings.

A fragment-based method was developed to investigate the binding conformations of peptide ligands. This method efficiently avoids the high degree of freedom (DOF) of peptide dockings by dividing a peptide into two half fragments. The fragments are separately docked on receptors and the results are used to rebuild a profile of massive possible docking conformations of the whole peptide.

Theoretical investigation on reaction of sulbactam with wild-type SHV-1 β-lactamase: acylation, tautomerization, and deacylation.

Molecular dynamics (MD) simulation and quantum mechanical (QM) calculations were used to investigate the reaction mechanism of sulbactam with class A wild-type SHV-1 β-lactamase including acylation, tautomerization, and deacylation. Five different sulbactam-enzyme configurations were investigated by MD simulations. In the acylation step, we found that Glu166 cannot activate Ser70 directly for attacking on the carbonyl carbon, and Lys73 would participate in the reaction acting as a relay.

Computer simulation to investigate the FRET application in DNA hybridization systems.

Molecular dynamics (MD) and quantum mechanics (QM) were used to investigate fluorescence resonance energy transfer (FRET) between coumarin and ethidium in two Mergny's DNA hybridization systems. By combining the transition dipoles calculated by the quantum semi-empirical method and the conformations of the FRET probes collected by MD, FRET efficiencies were derived from the Förster equation at five temperatures from 273 K to 313 K. The plotted efficiencies were compared with Mergny's experiments, and showed good agreement.

Enhanced recognition of single-base mismatch using locked nucleic acid-integrated hairpin DNA probes revealed by atomic force microscopy nanolithography.

Probe design is a critical parameter in successful DNA and RNA target detection. In this proof-of-concept study, we evaluated the single-base mismatch recognition power of surface immobilized and self-assembled stem-loop hairpin DNA oligonucleotide probes modified to contain locked nucleic acid residues (LNA-HP). The stiffness change in conjunction with the stem opening of the interfacial molecules before and after hybridization led to clear variations of the overall film thickness or miniaturized nanospot height, which could be directly measured using an atomic force microscopy (AFM) nanolithography technique.

Potential of mean force for Syrian hamster prion epitope protein--monoclonal fab 3f4 antibody interaction studies.

Simulating antigen-antibody interactions are crucial for understanding antigen-antibody associations in immunology. To shed further light on this question, we study a dissociation of the Syrian hamster prion epitope protein-fab 3f4 antibody complex structure. The stretching, that is, the distance between the center of mass of the prion epitope protein and the fab 3f4 antibody, has been studied using potential of mean force (PMF) calculations based on molecular dynamics (MD) and the implicit water model.