Predicting Pathways between Distant Configurations for Biomolecules.


Type
Article
Change log
Authors
Abstract

Many of the most interesting rearrangements associated with function and dysfunction of biomolecules involve complex, highly nonlinear pathways. Predicting these convoluted changes in structure is an important research challenge, since knowledge of key intermediate conformations at an atomic level of detail has the potential to inform the design of novel therapeutic strategies with enhanced specificity. The identification of kinetically relevant pathways can be strongly dependent on the construction of a physically relevant initial pathway between specified end points, avoiding artifacts such as chain crossings. In this contribution we describe an enhanced interpolation procedure to characterize initial pathways for complex rearrangements of a histone tail, α-helix to β-sheet conversion for amyloid-β17-42, and EGFR kinase activation. Complete connected initial pathways with relatively low overall barriers are obtained in each case using an enhanced quasi-continuous interpolation scheme. This approach will help to extend the complexity and time scales accessible to computer simulation.

Description
Keywords
Algorithms, Amyloid beta-Peptides, Computer Simulation, ErbB Receptors, Histones, Humans, Models, Molecular, Peptide Fragments, Protein Conformation, Protein Structure, Secondary
Journal Title
J Chem Theory Comput
Conference Name
Journal ISSN
1549-9618
1549-9626
Volume Title
14
Publisher
American Chemical Society (ACS)
Sponsorship
EPSRC (1652488)
Engineering and Physical Sciences Research Council (EP/N035003/1)