Detection of Allosteric Communication in NtrC using a Structural Alphabet analysis of Molecular Dynamics Trajectories


New research project

Leverhulme Trust Research Project Grant:

"An integrated computational-experimental method to redesign protein dynamics".

Using Local States To Drive the Sampling of Global Conformations in Proteins


Conformational changes associated with protein function often occur beyond the time scale currently accessible to unbiased molecular dynamics (MD) simulations, so that different approaches have been developed to accelerate their sampling.  Here we investigate how the knowledge of backbone conformations preferentially adopted by protein fragments, as contained in precalculated libraries known as structural alphabets (SA), can be used to explore the landscape of protein conformations in MD simulations. We find that (a) enhancing the sampling of native local states in both metadynamics and steered MD simulations allows the recovery of global folded states in small proteins; (b) folded states can still be recovered when the amount of information on the native local states is reduced by using a low-resolution version of the SA, where states are clustered into macrostates; and (c) sequences of SA states derived from collections of structural motifs can be used to sample alternative conformations of preselected protein regions. The present findings have potential impact on several applications, ranging from protein model refinement to protein folding and design.


Pandini A & Fornili A

J Chem Theory Comput 12(3):1368–1379, 2016

PubMed   CVSA

Diagram of Analyses Available in the GSATools

GSATools: analysis of allosteric communication and functional local motions using a Structural Alphabet


Motivation: GSATools is a free software package to analyze conformational ensembles and to detect functional motions in proteins by means of a structural alphabet. The software integrates with the widely used GROMACS simulation package and can generate a range of graphical outputs. Three applications can be supported: (i) investigation of the conformational variability of local structures; (ii) detection of allosteric communication; and (iii) identification of local regions that are critical for global functional motions. These analyses provide insights into the dynamics of proteins and allow for targeted design of functional mutants in theoretical and experimental studies.


Availability: The C source code of the GSATools, along with a set of pre-compiled binaries, is freely available under GNU General Public License.



Pandini A, Fornili A, Fraternali F, Kleinjung J

Bioinformatics 29(16):2053-2055, 2013

PubMed    GSATools

Model of the Allosteric Communication Subnetwork in NtrC

Detection of allosteric signal transmission by information-theoretic analysis of protein dynamics


Allostery offers a highly specific way to modulate protein function. Therefore, understanding this mechanism is of increasing interest for protein science and drug discovery. However, allosteric signal transmission is difficult to detect experimentally and to model because it is often mediated by local structural changes propagating along multiple pathways. To address this, we developed a method to identify communication pathways by an information-theoretical analysis of molecular dynamics simulations. Signal propagation was described as information exchange through a network of correlated local motions, modeled as transitions between canonical states of protein fragments. The method was used to describe allostery in two-component regulatory systems. In particular, the transmission from the allosteric site to the signaling surface of the receiver domain NtrC was shown to be mediated by a layer of hub residues. The location of hubs preferentially connected to the allosteric site was found in close agreement with key residues experimentally identified as involved in the signal transmission. The comparison with the networks of the homologues CheY and FixJ highlighted similarities in their dynamics. In particular, we showed that a preorganized network of fragment connections between the allosteric and functional sites exists already in the inactive state of all three proteins.


Pandini A, Fornili A, Fraternali F, Kleinjung J

FASEB J 26(2):868-81, 2012