Molecular dynamics simulations on the interactions between nucleic acids and a phospholipid bilayer

Recently,lipid nanoparticles(LNPs)have been extensively investigated as non-viral carriers of nucleic acid vaccines due to their high transport efficiency,safety,and straightforward production and scalability.However,the molecular mechanism underlying the interactions between nucleic acids and phospholipid bilayers within LNPs remains elusive.In this study,we employed the all-atom molecular dynamics simulation to investigate the interactions between single-stranded nucleic acids and a phospholipid bilayer.Our findings revealed that hydrophilic bases,specifically G in single-stranded RNA(ssRNA)and single-stranded DNA(ssDNA),displayed a higher propensity to form hydrogen bonds with phospholipid head groups.Notably,ssRNA exhibited stronger binding energy than ssDNA.Furthermore,divalent ions,particularly Ca2+,facilitated the binding of ssRNA to phospholipids due to their higher binding energy and lower dissociation rate from phospholipids.Overall,our study provides valuable insights into the molecular mechanisms underlying nucleic acidphospholipid interactions,with potential implications for the nucleic acids in biotherapies,particularly in the context of lipid carriers.

Molecular Insights into Striking Antibody Evasion of SARS-CoV-2 Omicron Variant

The SARS-CoV-2 Omicron variant has become the dominant variant in the world.Uncovering the structural basis of altered immune response and enhanced transmission of Omicron is particularly important.Here,taking twenty-five antibodies from four groups as examples,we comprehensively reveal the underlying mechanism of how mutations in Omicron induces the weak neutralization by using molecular simulations.Overall,the binding strength of 68%antibodies is weakened in Omicron,much larger than that in Delta(40%).Specifically,the percentage of the weakened antibodies vary largely in different groups.Moreover,the mutation-induced repulsion is mainly responsive for the weak neutralization in AB/CD groups but does not take effect in EF group.Significantly,we demonstrate that the disappearance of hydrophobic interaction and salt bridges due to residue deletions contributes to the decreased binding energy in NTD group.This work provides unprecedented atomistic details for the distinct neutralization of WT/Delta/Omicron,which informs prospective efforts to design antibodies/vaccines against Omicron.

Evaluation on performance of MM/PBSA in nucleic acid-protein systems

The molecular mechanics/Poisson-Boltzmann surface area(MM/PBSA) method has been widely used in predicting the binding affinity among ligands,proteins,and nucleic acids.However,the accuracy of the predicted binding energy by the standard MM/PBSA is not always good,especially in highly charged systems.In this work,we take the protein-nucleic acid complexes as an example,and showed that the use of screening electrostatic energy(instead of Coulomb electrostatic energy) in molecular mechanics can greatly improve the performance of MM/PBSA.In particular,the Pearson correlation coefficient of dataset Ⅱ in the modified MM/PBSA(i.e.,screening MM/PBSA) is about 0.52,much better than that(<0.33)in the standard MM/PBSA.Further,we also evaluate the effect of solute dielectric constant and salt concentration on the performance of the screening MM/PBSA.The present study highlights the potential power of the screening MM/PBSA for predicting the binding energy in highly charged bio-systems.

Accurate Evaluation on the Interactions of SARS-CoV-2 with Its Receptor ACE2and Antibodies CR3022/CB6

The spread of the coronavirus disease 2019(COVID-19) caused by severe acute respiratory syndrome coronavirus-2(SARS-CoV-2) has become a global health crisis.The binding affinity of SARS-CoV-2(in particular the receptor binding domain,RBD) to its receptor angiotensin converting enzyme 2(ACE2) and the antibodies is of great importance in understanding the infectivity of COVID-19 and evaluating the candidate therapeutic for COVID-19.We propose a new method based on molecular mechanics/Poisson-Boltzmann surface area(MM/PBSA) to accurately calculate the free energy of SARS-CoV-2 RBD binding to ACE2 and antibodies.The calculated binding free energy of SARS-CoV-2 RBD to ACE2 is-13.3 kcal/mol,and that of SARS-CoV RBD to ACE2 is-11.4 kcal/mol,which agree well with the experimental results of-11.3 kcal/mol and-10.1 kcal/mol,respectively.Moreover,we take two recently reported antibodies as examples,and calculate the free energy of antibodies binding to SARS-CoV-2 RBD,which is also consistent with the experimental findings.Further,within the framework of the modified MM/PBSA,we determine the key residues and the main driving forces for the SARS-CoV-2 RBD/CB6 interaction by the computational alanine scanning method.The present study offers a computationally efficient and numerically reliable method to evaluate the free energy of SARS-CoV-2 binding to other proteins,which may stimulate the development of the therapeutics against the COVID-19 disease in real applications.

铂···铂相互作用诱导逐级自组装促进圆偏振光信号放大

高效圆偏振发光材料在传感、光学器件、不对称合成等领域有着广泛的应用,设计和制备圆偏振发光材料引起了人们的广泛关注.然而,构筑具有高发光不对称因子的圆偏振发光材料仍然是一个挑战.这里,我们制备了一种手性超分子组装金属大环,该超分子组装金属大环可以通过分子间铂···铂相互作用诱导逐级自组装促进圆偏振光的放大.值得注意的是,超分子组装金属大环显示出高的发光不对称因子以及较强的圆偏振光信号,而其对应的组装配体没有显示出圆偏振光信号.通过紫外-可见吸收光谱和发射光谱、核磁共振氢谱、扫描电镜、透射电镜、原子力显微镜、粗粒化分子动力学模拟和含时密度泛函理论计算等手段对圆偏振光放大的机理进行了研究.该研究展示了第一例基于铂···铂相互作用驱动的逐级自组装策略制备的高效圆偏振发光材料.

Construction of Metallacycle-Linked Heteroarm Star Polymers via Orthogonal Post-Assembly Polymerization and Their Intriguing Self-Assembly into Large-Area and Regular Nanocubes

of main observation and conclusion In recent years,synthesis of hybrid heteroarm star polymer with precisely defined arms has evolved to be one of the most attractive topics within polymer chemistry.In this study,we present the successful synthesis of metallacycle-linked heteroarm star polymers(HASPs)composed of crystalline poly(e-caprolactone)(PCL)and polyacrylate(poly(N-isopropylacrylamide)(PNIPAM)segments via combination of ring-opening polymerization(ROP)and reversible addition-fragmentation chain transfer(RAFT)controlled radical polymerization.Firstly,a hexagonal metallacycle containing three hydroxy groups and three chain transfer agent moieties at the alternative vertexes was designed and synthesized based on the general principle of coordination-driven self-assembly.Subsequently,upon combination of two orthogonal post-assembly polymerizations,a new family of HASPs containing a well-defined hexagonal metallacycle with precisely controlled position of polymer arms was facilely prepared.Interestingly,the obtained HASPs could spontaneously self-assemble into large-area and regular cubic nanoparticles in tetrahydrofuran(THF)/methanol(MeOH)mixed solvents under specific conditions as confirmed by scanning electron microscopy(SEM)and atomic force microscopy(AFM).This study provides a simple route to the controllable preparation of HASPs,and opens up a new way for further study on self-assembly of different HASPs systems.