Scientific Background

In the last few decades molecular dynamics (MD) simulations have become an indispensable tool for mechanistic analysis in structural biology. From its first applications, revealing the fluid-like interior of protein that result from the diffusional character of local atomic motion, to more recent applications simulating entire organelles, the information content generated by MD studies has grown rapidly. With the increase of system sizes and the frequent use of enhanced sampling techniques, came the need for new and enhanced analysis tools, capable of extracting information from massive amounts of data and generating new insight.

Developed just over a decade ago, a particularly interesting technique that has recently become popular is the analysis of dynamical networks. This technique has been employed to study how groups of atoms interconnect in communities, and also the allosteric signaling in tRNA:protein complexes, glutamine amidotransferase, and many other systems.

The analysis of networks and their properties has a long history, with applications in diverse fields such as engineering, and social networks, and their approach to modelling molecular systems is particularly fruitful, leading to a rich field of research. Using MD simulations to extract dynamical features from biomolecules, from simple proteins to complexes, one can convert the atomic representation of the system into a nodes-and-edges representation that can then be analyzed much like any other graph. A key source of information is the partitioning of the network in subgroups (or communities) using algorithms such as Girvan-Newman’s, providing information on cooperative motion within a protein’s subdomains, or on residues that mediate communication between communities. Both are computationally challenging tasks, and can become very expensive as the size of the network grows.

Dynamical Network Analysis

The approach take in Dynamical Network Analysis is one based on the correlation of movement of representative atoms (or nodes), such as alpha-carbons of amino acid residues. This serves as a measurement to determine the existence and strength of a link between different atoms or molecules of a system.

Each node represents a set of atoms of a given residue, and there may be more than one node per residue. By default, amino acid residues are represented by a single node located in their alpha-carbons, and nucleotides by two nodes, one in the backbone phosphate, and one in the nitrogenous base. Water molecules have one node in their oxygen atom, and ions are trivially represented by one node.

The analysis performed here focuses solely on the correlation of movement of nodes in close proximity. This way, only short-range direct interactions are explicitly calculated, and long range interactions are determined through the analysis of the network itself.

To determine which nodes are in contact, the shortest distance between heavy atoms (all atoms excluding hydrogen atoms) represented by two nodes is calculated. If the distance is shorter than 4.5 Angstroms in a simulation frame, the pair of nodes is said to be in contact in that frame. If a pair of nodes is in contact in more than 75% of a simulation, they are considered to be in contact for the purposes of network analysis.

After determining all nodes in contact throughout a simulation, and calculating the correlation of motion between them, the network can then be visualized (see Image 1).

Rendering of protein and network.

Networks analysis of OMP-decarboxylase. (a) Full network revealing the most correlated regions of the enzyme. The weight of the network edges (represented by thickness of red tubes) is given by its normalized generalized correlation coefficient. (b) Rendering showing communities and betweenness values of edges of the OMP-decarboxylase dynamic network. Communities are delineated by the different colors of the protein secondary structure, while betweenness values of network edges are indicated by the thickness red tubes. Both images were rendered with VMD using the new Network Viewer 2.0 GUI.

Current Implementation

This package was built to provide all functionalities necessary to the analysis of MD simulations using the Dynamical Network Analysis method. In particular, it accelerates the calcualtion of generalized correlation coefficients by first calculating a contact matrix for the network, and then parallelizing the correlation calculation only for the pairs of nodes in contact. This can save over 99% of the computational cost of generalized correlation calculations.