New insight into the traditional model of the coagulation cascade and its regulation: illustrated review of a three-dimensional view.

The coagulation process relies on an intricate network of three-dimensional structural interactions and subtle biological regulations. In the present review, we illustrate the state of the art of the structural biology of the coagulation cascade by surveying the Protein Data Bank and the EBI AlphaFold databases. Investigations performed in the last decade have provided structural information on essentially all players involved in the process. Indeed, the initial characterization of specific and rather canonical domains has been progressively extended to complicated multidomain proteins. Recently, the application of cryogenic electron microscopy techniques has unraveled the structural features of highly complex coagulation factors, which has led to enhanced understanding. This review initially focuses on the structure of the individual factors as a function of their involvement in intrinsic, extrinsic, and common pathways. A specific emphasis is given to what is known or unknown on the structural basis of each step of the cascade. Available data providing clues on the structural recognition of the factors involved in the functional partnerships of the pathways are illustrated. Recent structures of important complexes formed by these proteins with regulators are described, focusing on the drugs used as anticoagulants and on their reversal agents. Finally, we highlight the different roles that innovative biomolecules such as aptamers may have in the regulation of the cascade.

Conformational studies of chiral D-Lys-PNA and achiral PNA system in binding with DNA or RNA through a molecular dynamics approach.

The growing interest in peptide nucleic acid (PNA) oligomers has led to the development of a very wide variety of PNA derivatives. Among others, the introduction of charged chiral groups on a PNA oligomer has proven effective in improving DNA binding ability, complexation direction and cellular uptake. In particular, the introduction of three adjacent chiral monomers based on D-Lys in the middle of the PNA sequence (D-Lys-PNA) has produced noteworthy results in modulating the directionality of the binding with the DNA complementary strand and in mismatch detection. Here, through a molecular dynamics approach, a comparative study has been carried out to investigate the structural properties that drive the interaction of the chiral D-Lys-PNA and the corresponding achiral PNA system with DNA as well as RNA complementary strands, starting from the crystal structure of D-Lys-PNA in complex with DNA. The results obtained complement experimental data and indicate that the binding with the RNA molecule, compared to DNA, is differently affected by the addition of three D-Lys groups on the PNA backbone, suggesting that this modification could be taken into account for the development of new PNA-based molecules able to discriminate between DNA and RNA.