MDO: A Computational Protocol for Accurate Prediction of Full Flexibility Receptor-Ligand Binding Mode Structures

Predicting the binding structure of bio-complex is essential for understanding its properties, functions, and mechanisms, but is rather difficult due to the huge sampling space involved. A new computational protocol, MDO, for finding the ligand binding structure is proposed. MDO consists of global sampling via MD simulation and clustering of the receptor configurations, local sampling via molecular docking and clustering of the ligand conformations, and binding structure optimization by the ONIOM (QM/QM) method. MDO is tested on 15 protein-ligand complexes with known accurate structures. The success rate of MDO predictions, with RMSD < 2 Å, is found to be 67%, substantially higher than the 40% success rate of conventional methods. The MDO success rate can be increased to 83% if the ONIOM calculations are applied only for the starting poses with ligands inside the binding cavities. The MDO protocol is a promising tool for the structure based drug design.

A cocrystal structure of dengue capsid protein in complex of inhibitor

Dengue virus (DENV) was designated as a top 10 public health threat by the World Health Organization in 2019. No clinically approved anti-DENV drug is currently available. Here we report the high-resolution cocrystal structure (1.5 Å) of the DENV-2 capsid protein in complex with an inhibitor that potently suppresses DENV-2 but not other DENV serotypes. The inhibitor induces a “kissing” interaction between two capsid dimers. The inhibitor-bound capsid tetramers are assembled inside virions, resulting in defective uncoating of nucleocapsid when infecting new cells. Resistant DENV-2 emerges through one mutation that abolishes hydrogen bonds in the capsid structure, leading to a loss of compound binding. Structure-based analysis has defined the amino acids responsible for the inhibitor’s inefficacy against other DENV serotypes. The results have uncovered an antiviral mechanism through inhibitor-induced tetramerization of the viral capsid and provided essential structural and functional knowledge for rational design of panserotype DENV capsid inhibitors.

Possible roles for semantics and syntax in a government-binding structure

As described, for example, by Hornstein, the general linguistic framework given by the contemporary government-binding theory distinguishes several levels. This paper is intended to show that a differentiation of that kind, if such levels are understood in a different manner, can be clearly consistent with some developments in current cognitive science, and, in particular, with approaches such as the one of López-Astorga, which attempts to link proposals that, in principle, can be deemed as irreconcilable, such as the mental models theory and the idea that human cognition is led by logical forms. In this way, without accepting the characteristics that usually are assigned to the levels pointed out by the government-binding theory, it is argued that the role attributed to semantics and syntax by López-Astorga can be compatible with a general structure more or less akin to the one of this last theory.