Samuel Coulbourn Flores Lab

Structural Bioinformatics and computational structural biology

 
 

MacroMoleculeBuilder (MMB), written by the PI, is a multiresolution modeling tool for building 3D structural and dynamical models of macromolecules. It gives you explicit control over the degrees of freedom, forces, constraints, and molecules in your system..Published applications include predicting the effect of mutations on protein-protein interactions, in silico affinity maturation, RNA folding from biochemical data, homology modeling, flexible fitting into electron density maps, morphing, and fast prototype simulations of large complexes.




CURRENT PROJECTS




RNA


The flexibility of large RNAs presents a significant challenge to understanding large complexes such as the ribosome, and to designing complexes for nanotechnology. Previously,  MMB has successfully folded tRNA and the P4/P6 domain of the Group I Intron, threaded the Azoarcus Group I Intron, explained the role of disease associated mutations in telomerase, and modeled all-atoms trajectories of ribosomal translocation. We are currently working on ribosomal frameshifting and GTP hydrolysis on EF-G, as well as the mechanism of intersubunit specificity in erythromycin (antibiotic) synthesis on DEBS. We are have also built a Graphical User Interface to make MMB accessible to a wider audience.





IN SILICO DESIGN OF BIOLOGICS


MMB offers a strategically important means of redesigning biologics (monoclonal antibodies or alternative scaffolds) in silico. It accounts for backbone flexibility by employing one or more small flexibility zones in internal coordinates. Then it computes dynamics taking into account physical interactions only within the physics zone -- a small spatial neighborhood about each flexible zone. A KB potential is used to evaluate the energies. The approach is economical, while still permitting most of the relevant backbone motions. We are using this to design therapies against autoimmune diseases and cancer.

 

Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi, Uppsala Biomedicinska Centrum