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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. To achieve maximal effect, a pro‐Ab must have high antigen‐blocking and protease‐restoring efficiencies, but the unclear structure limits its further optimization. Here, we utilized molecular dynamics (MD) simulations to study the dynamic structures of a hinge‐based Ab lock pro‐Ab, pro‐Nivolumab, and validated the simulated structures with small‐ and wide‐angle X‐ray scattering (SWAXS). The MD results were closely consistent with SWAXS data (χ2best‐fit = 1.845, χ2allMD = 3.080). The further analysis shows a pronounced flexibility of the Ab lock (root‐mean‐square deviation = 10.90 Å), yet it still masks the important antigen‐binding residues by 57.3%–88.4%, explaining its 250‐folded antigen‐blocking efficiency. The introduced protease accessible surface area method affirmed better protease efficiency for light chain (33.03 Å2) over heavy chain (5.06 Å2), which aligns with the experiments. Overall, we developed MD‐SWAXS validation method to study the dynamics of flexible blocking segments and introduced methodologies to estimate their antigen‐blocking and protease‐restoring efficiencies, which would potentially be advancing the clinical applications of any spatial hindrance‐based pro‐Ab. [ABSTRACT FROM AUTHOR]

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. However, the binding mechanisms between Nirmatrelvir and 3CLpro complex structures remain unknown. This study incorporated ligand Gaussian accelerated molecular dynamics, the one-dimensional and two-dimensional potential of mean force, normal molecular dynamics, and Kramers' rate theory to determine the binding and dissociation rate constants (koff and kon) associated with the binding of the 3CLpro protein to the Nirmatrelvir inhibitor. The proposed approach addresses the challenges in designing small-molecule antiviral drugs. [ABSTRACT FROM AUTHOR]

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. Particularly, LNA-HP achieved highly differentiable readouts between perfectly complementary and singly mismatched targets (discrimination ratio as high as 2 to 3), outperforming the selectivity of its linear and hairpin counterparts with no LNA modification. 10.1021/ac902665c

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. Through rapid scoring for filtering, the remaining peptide docking conformations are rigorously optimized by molecular dynamics (MD) and scored by molecular mechanics/generalized born surface area (MM/GBSA) method to predict the near-native binding conformations. This method has been tested on 17 cases of long peptide–protein interaction with known crystal structures, and also on 7 unbound protein receptors for which both the bound and unbound conformations are known. The resultant binding predictions fit very closely to the crystal structures. [ABSTRACT FROM AUTHOR]

Dissipative particle dynamics (DPD) was carried out to study the copolymerization process of halogen-substituted styrene (ST-X), divinylbenzene (DVB), and dodecane (DO) in aqueous solution. The results showed that properly selecting the sizes of DO and water beads, and choosing the appropriate interaction parameters between beads are crucial in the simulation system. The influence of polymerization parameters, such as polymerization temperature, ST-X/DVB/DO/water ratio, and halogen substitution on ST on the copolymer morphology, were investigated in detail and confirmed that the simulation results can reproduce the macroscopic experimental phase separation. In addition, the pore volume of copolymers formed at different polymerization conditions is estimated, which consisted with the data measured in the experiments. Our work has demonstrated that DPD methods can be applied to study such copolymerization process. [ABSTRACT FROM AUTHOR]

Dissipative particle dynamics (DPD) was carried out to study the nucleation and crystal growth process of cerium dioxide (CeO2) nanoparticles in alcohol/water mixed solvents by homogeneous precipitation method. The results showed that properly selecting the sizes of CeO2 and water beads, and choosing the appropriate interaction parameters between beads are crucial in the simulation system. The nucleation and crystal growth process of CeO2 can be classified into four stages: induction, nuclei growth, crystal forming, and crystal aggregation, which could be reproduced from different initial CeO2 concentration and after different simulation time. The simulation results confirm that the effect of solvent on the nucleation and crystal growth of CeO2 nanoparticles are different at four stages and cannot be simply described by Derjaguin–Landau–Verwey–Overbeek theory or nucleation thermodynamics theory as proposed in the published literatures. Our work demonstrated that DPD methods can be applied to study nanoparticle forming process. [ABSTRACT FROM AUTHOR]

Molecular mechanics (MM) method followed by molecular dynamics (MD) simulation was carried out to investigate the stability of an aggregate formed by self-assembling of peptide amphiphile (PA) molecules. The MM + MD simulation confirms that the cylindrical shaped aggregate is very stable. The analysis showed that the remarkable stability of the aggregate was partly due to various intermolecular hydrogen-bond interactions between polar groups of PA molecules. The hydrophobic alkyl tails of PA molecules are packed loosely inside the interior of the aggregates. The packing of alkyl tails contribute further stability of the PA aggregate. Our simulations reproduce qualitatively experimental observations and support the fact that PA molecules are self-assembled within closed intermolecular distance to favor the forming of disulfide bonds. [ABSTRACT FROM AUTHOR]

Molecular dynamics simulation with a modified CHARMM (Chemistry at Harvard Macromolecular Mechanics) force field was carried out to investigate the properties of chrome-tanned collagen in comparison with chrome-free collagen under hydrated and dehydrated conditions. An attempt has been made to explain the microcosmic origins of the various properties of the chromium(III)-crosslinked collagen. The present simulation describes the clear crosslinking topology of polychromiums to peptide chains, identifies the linking site and the capacity of the linkage, explains why the efficiency is not 100% in a practical tanning process and provides a new viewpoint on the crosslinking of the polychromium with the side chains of the collagen. [ABSTRACT FROM AUTHOR]