Unveiling the multicomponent phase separation through molecular dynamics simulation and graph theory.

Biomolecular condensates formed by multicomponent phase separation play crucial roles in diverse cellular processes. Accurate assessment of individual-molecule contributions to condensate formation and precise characterization of their spatial organization within condensates are crucial for understanding the underlying mechanism of phase separation. Using molecular dynamics simulations and graph theoretical analysis, we demonstrated quantitatively the significant roles of cation-π and π-π interactions mediated by aromatic residues and arginine in the formation of condensates in polypeptide systems. Our findings reveal temperature and chain length-dependent alterations in condensate network parameters, such as the number of condensate network layers, and changes in aggregation and connectivity. Notably, we observe a transition between assortativity and disassortativity in the condensate network. Moreover, polypeptides W, Y, F, and R consistently promote condensate formation, while the contributions of other charged and two polar polypeptides (Q and N) to condensate formation depend on temperature and chain length. Furthermore, polyadenosine and polyguanosine can establish stable connections with aromatic and R polypeptides, resulting in the reduced involvement of K, E, D, Q, and N in phase separation. Overall, this study provides a distinctive, precise, and quantitative approach to characterize the multicomponent phase separation.

Topology- and size-dependent binding of DNA nanostructures to the DNase I.

The susceptibility of DNA nanomaterials to enzymatic degradation in biological environments is a significant obstacle limiting their broad applications in biomedicine. While DNA nanostructures exhibit some resistance to nuclease degradation, the underlying mechanism of this resistance remains elusive. In this study, the interaction of tetrahedral DNA nanostructures (TDNs) and double-stranded DNA (dsDNA) with DNase I is investigated using all-atom molecular dynamics simulations. Our results indicate that DNase I can effectively bind to all dsDNA molecules, and certain key residues strongly interact with the nucleic bases of DNA. However, the binding of DNase I to TDNs exhibits a non-monotonic behavior based on size; TDN15 and TDN26 interact weakly with DNase I (∼ - 75 kcal/mol), whereas TDN21 forms a strong binding with DNase I (∼ - 110 kcal/mol). Furthermore, the topological properties of the DNA nanostructures are analyzed, and an under-twisting (∼32°) of the DNA helix is observed in TDN15 and TDN26. Importantly, this under-twisting results in an increased width of the minor groove in TDN15 and TDN26, which primarily explains their reduced binding affinity to DNase I comparing to the dsDNA. Overall, this study demonstrated a novel mechanism for local structural control of DNA at the nanoscale by adjusting the twisting induced by length.

Effect of Terahertz Waves on the Structure of the Aß42 Monomer, Dimer, and Protofibril: Insights from Molecular Dynamics Simulations.

Amyloid-ß (Aß) and its assemblies play important roles in the pathogenesis of Alzheimer's disease (AD). Recent studies conducted by experimental and computational researchers have extensively explored the structure, assembly, and influence of biomolecules and cell membranes on Aß. However, the impact of terahertz waves on the structures of Aß monomers and aggregates remains largely unexplored. In this study, we systematically investigate the molecular mechanisms by which terahertz waves affect the structure of the Aß42 monomer, dimer, and tetramer through all-atom molecular dynamics (MD) simulations. Our findings indicate that terahertz waves at a specific frequency (42.55 THz) can enhance intramolecular and intermolecular interactions in the Aß42 monomer and dimer, respectively, by resonating with the symmetric stretching mode of the -COO- groups and the symmetric bending/stretching mode of -CH3 groups. Consequently, the ß-structure content of the Aß42 monomer is greatly increased, and the binding energy between the monomers in the Aß42 dimer is significantly enhanced. Additionally, our observations suggest that terahertz waves can mildly stabilize the structure of tetrameric protofibrils by enhancing the interactions among peripheral peptides. Furthermore, we also investigated the effect of the frequency of terahertz waves on the structure of Aß42. The present study contributes to a better understanding of the impact of external fields on the biobehavior of Aß42 peptides and may shed some light on the potential risks associated with electromagnetic field radiation.

Effect of maleylation and denaturation of human serum albumin on its interaction with scavenger receptors.

The specific recognition of serum proteins by scavenger receptors is critical and fundamental in many biological processes. However, the underlying mechanism of scavenger receptor-serum protein interaction remains elusive. In this work, taking scavenger receptors class A1 (SR-A1) as an example, we systematically investigate its interaction with human serum albumin (HSA) at different states through a combination of molecular docking and all-atom molecular dynamics simulations. It is found that native HSA can moderately bind to collagen-like (CL) region or scavenger receptor cysteine-rich (SRCR) region, with both electrostatic (ELE) and van der Waals (VDW) interactions, playing important roles. After maleylation, the binding energy, particularly the ELE energy, between HSA and CL region is significantly enhanced, while the binding energy between HSA and SRCR region remains nearly unchanged. Additionally, we also observe that unfolding of the secondary structures in HSA leads to a larger contact surface area between denatured HSA and CL region, but has little impact on the HSA-SRCR region interaction. Therefore, similar to maleylated HSA, denatured HSA is also more likely to bind to the CL region of SR-A1.

Effect of the Graphene Nanosheet on Functions of the Spike Protein in Open and Closed States: Comparison between SARS-CoV-2 Wild Type and the Omicron Variant.

The spread of coronavirus disease 2019 caused by SARS-CoV-2 and its variants has become a global health crisis. Although there were many attempts to use nanomaterials-based devices to fight against SARS-CoV-2, it still remains elusive as to how the nanomaterials interact with SARS-CoV-2 and affect its biofunctions. Here, taking the graphene nanosheet (GN) as the model nanomaterial, we investigate its interaction with the spike protein in both WT and Omicron by molecular simulations. In the closed state, the GN can insert into the region between the receptor binding domain (RBD) and the N-terminal domain (NTD) in both wild type (WT) and Omicron, which keeps the RBD in the down conformation. In the open state, the GN can hamper the binding of up RBD to ACE2 in WT, but it has little impact on up RBD and, even worse, stimulates the down-to-up transition of down RBDs in Omicron. Moreover, the GN can insert in the vicinity of the fusion peptide in both WT and Omicron and prevents the detachment of S1 from the whole spike protein. The present study reveals the effect of the SARS-CoV-2 variant on the nanomaterial-spike protein interaction, which informs prospective efforts to design functional nanomaterials against SARS-CoV-2.