9 research outputs found
Normal-Mode-AnalysisâMonitored Energy Minimization Procedure for Generating SmallâMolecule Bound Conformations
The energy minimization of a small molecule alone does not automatically stop at a local minimum of the potential energy surface of the molecule if the minimum is shallow, thus leading to folding of the molecule and consequently hampering the generation of the bound conformation of a guest in the absence of its host. This questions the practicality of virtual screening methods that use conformations at local minima of their potential energy surfaces (local minimum conformations) as potential bound conformations. Here we report a normal-mode-analysisâmonitored energy minimization (NEM) procedure that generates local minimum conformations as potential bound conformations. Of 22 selected guestâhost complex crystal structures with guest structures possessing up to four rotatable bonds, all complexes were reproduced, with guest massâweighted root mean square deviations of <1.0 Ă
, through docking with the NEMâgenerated guest local minimum conformations. An analysis of the potential energies of these local minimum conformations showed that 22 (100%), 18 (82%), 16 (73%), and 12 (55%) of the 22 guest bound conformations in the crystal structures had conformational strain energies of less than or equal to 3.8, 2.0, 0.6, and 0.0 kcal/mol, respectively. These results suggest that (1) the NEM procedure can generate smallâmolecule bound conformations, and (2) guests adopt low-strainâenergy conformations for complexation, thus supporting the virtual screening methods that use local minimum conformations
Growing Smart Cities
As the worldâs population becomes increasingly urbanised the problems of building sustainable cities also grows. Using Susan Stepneyâs response, âMighty Oaks from Little Acorns Growâ, to a science fiction story by Adam Marek titled âGrowing Skyscrapersâ, this chapter looks at what a living city of the future might look like, and how that might solve some of the problems of the control and development of cities. There is a long history of the application of systems thinking, cybernetics, and complex systems and the growth and control of cities. However, many problems still remain in the deployment and applications of these frameworks and methodologies, and in the potential consequences of their use. However, perhaps many of these could be solved by the development of a living city
Conserved patterns hidden within group A Streptococcus M protein hypervariability recognize human C4b-binding protein
No vaccine exists against group A Streptococcus (GAS), a leading cause of worldwide morbidity and mortality. A severe hurdle is the hypervariability of its major antigen, the M protein, with >200 different M types known. Neutralizing antibodies typically recognize M protein hypervariable regions (HVRs) and confer narrow protection. In stark contrast, human C4b-binding protein (C4BP), which is recruited to the GAS surface to block phagocytic killing, interacts with a remarkably large number of M protein HVRs (apparently âŒ90%). Such broad recognition is rare, and we discovered a unique mechanism for this through the structure determination of four sequence-diverse M proteins in complexes with C4BP. The structures revealed a uniform and tolerant 'reading head' in C4BP, which detected conserved sequence patterns hidden within hypervariability. Our results open up possibilities for rational therapies that target the M-C4BP interaction, and also inform a path towards vaccine design