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.
Highlights
IntroductionThe potential energy landscape of a molecule encodes all the information necessary to understand its thermodynamic, kinetic, and structural properties.[1−5] efficient methods to explore this landscape represent an active research field.[6]
The potential energy landscape of a molecule encodes all the information necessary to understand its thermodynamic, kinetic, and structural properties.[1−5] efficient methods to explore this landscape represent an active research field.[6]Biomolecules such as proteins, RNA and DNA are the targets of many theoretical and experimental studies due to their central role in the chemistry of life and disease
The histone tail conformations were taken from replica-exchange molecular dynamics simulations (REMD).[54]
Summary
The potential energy landscape of a molecule encodes all the information necessary to understand its thermodynamic, kinetic, and structural properties.[1−5] efficient methods to explore this landscape represent an active research field.[6] Biomolecules such as proteins, RNA and DNA are the targets of many theoretical and experimental studies due to their central role in the chemistry of life and disease. In experiment and simulation a multitude of relaxation time scales may be observed for biomolecules if the time resolution is short enough These time scales result from the large range of barrier heights on the landscape, where the highest barriers are usually associated with the slowest rate-determining steps that determine function. The presence of high barriers can lead to broken ergodicity, and enhanced sampling methods are generally required in simulations to provide experimentally relevant results
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