scholarly journals Atomistic picture of conformational exchange in a T4 lysozyme cavity mutant: an experiment-guided molecular dynamics study

2016 ◽  
Vol 7 (6) ◽  
pp. 3602-3613 ◽  
Author(s):  
Pramodh Vallurupalli ◽  
Nilmadhab Chakrabarti ◽  
Régis Pomès ◽  
Lewis E. Kay
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Relaxation Dispersion ◽  
Conformational Exchange ◽  
T4 Lysozyme ◽  
Nmr Techniques ◽  
Relaxation Dispersion Nmr ◽  
Dynamics Simulations

Relaxation-dispersion NMR techniques and molecular dynamics simulations have been used to understand how a cavity mutant of T4 lysozyme interconverts between two compact conformations.

scholarly journals Mapping transiently formed and sparsely populated conformations on a complex energy landscape

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Yong Wang ◽  
Elena Papaleo ◽  
Kresten Lindorff-Larsen
Keyword(s):  
Energy Landscape ◽  
Nmr Relaxation ◽  
Relaxation Dispersion ◽  
Conformational Exchange ◽  
Internal Cavity ◽  
T4 Lysozyme ◽  
Enhanced Sampling ◽  
Exchange Processes ◽  
Dynamics Simulations ◽  
A Minor

Determining the structures, kinetics, thermodynamics and mechanisms that underlie conformational exchange processes in proteins remains extremely difficult. Only in favourable cases is it possible to provide atomic-level descriptions of sparsely populated and transiently formed alternative conformations. Here we benchmark the ability of enhanced-sampling molecular dynamics simulations to determine the free energy landscape of the L99A cavity mutant of T4 lysozyme. We find that the simulations capture key properties previously measured by NMR relaxation dispersion methods including the structure of a minor conformation, the kinetics and thermodynamics of conformational exchange, and the effect of mutations. We discover a new tunnel that involves the transient exposure towards the solvent of an internal cavity, and show it to be relevant for ligand escape. Together, our results provide a comprehensive view of the structural landscape of a protein, and point forward to studies of conformational exchange in systems that are less characterized experimentally.

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