Content-guided Navigation in Multimeric Molecular Complexes

Mikael Trellet

, Nicolas Ferey

, Marc Baaden

and Patrick Bourdot

VENISE group, LIMSI (CNRS), University Paris-Sud, Rue John Von Neumann, Orsay, France

LBT-IBPC (CNRS), University Paris Diderot, Paris, France

Keywords: Molecular Visualization, Constrained Navigation, Structural Biology.

Abstract: In the field of structural biology, molecular visualization is a critical step to study and understand 3D

structures generated by experimental and theoretical technics. Numerous programs are dedicated to the

exploration and analysis of structures in 3 dimensions. However, very few of them offer navigation

algorithms that deal in an intelligent way with the content they display and the task to perform. This

observation is emphasized in the case of navigation in immersive environments where users are immersed in

their molecular systems, without any spatial landmark to guide their exploration. Starting from this

observation, we propose to take into account some geometrical features found in multimeric molecular

complexes to provide navigation guides to the users during the exploration process. It is possible thanks to

the common symmetrical layout molecular complexes present. Beyond the biological meaning and

importance that symmetric layouts have in proteins, they allow us to orient and guide the exploration of

molecular complexes in an intelligent and meaningful manner. We present then a current work on the design

of navigation paradigms based on the content and the task for the molecular visualization.

1 INTRODUCTION

Structural biology can be split into several

indispensable steps that lead to the deciphering of

molecular complexes. One of these steps is the

visualization and exploration of molecular

structures. Several technics are able to generate

accurate 3-dimensional structures of molecules. One

can cite NMR and X-ray as well as molecular

modelling programs to be part of the top structure

generators. To fully understand the function and the

role that structure plays in molecular functions, no

one can pass by the visualization step. Broadly used

programs of molecular visualization display 3D

structures of molecules in a very efficient way.

However, only poor efforts were put in the

navigation paradigms use to explore such 3D

models. Two things can explain this: Firstly, until a

very recent period, molecular systems were quite

reduced in terms of size and their exploration did not

require any complicated algorithms. Secondly,

visualization of molecular systems in immersive

environments or with stereoscopic solutions was not

possible or very limited. However, these two points

are now outdated. It is now possible to generate

accurate models of molecular systems with more

than several hundreds of thousands of atoms.

Moreover, some laboratories investigate other ways

to render and interact with their 3D models. They

aim to put the scientist in the center of its

exploration, bringing the ensemble of his senses

focus on his task using multimodal rendering (Férey

et al., 2009). Stereoscopic solutions as well as

intuitive and natural ways to interact with a

molecular system are used in this purpose. Several

works on the intake of such immersive environments

for the scientific visualization have been made (Van

Dam et al., 2000). Numerous issues linked to the

navigation in immersive environments were

addressed along the last years (Christie et al., 2008)

but rarely by taking into account both the content of

the scene and the tasks that will be performed in it.

This immersion goes together with perception

issues. Several studies have been made to evaluate

the impact of immersive technics during the

exploration of virtual scenes. When dealing with

oriented and realistic environments, user comfort

can be quite well managed. However, the

exploration of abstract scientific data, where no

implicit or explicit orientations exist, raises several

issues when coming to the user experience and

efficiency. Simple navigation tasks can be perturbed

Trellet M., Ferey N., Baaden M. and Bourdot P..

Content-guided Navigation in Multimeric Molecular Complexes.

DOI: 10.5220/0004914300760081

In Proceedings of the International Conference on Bioimaging (BIOIMAGING-2014), pages 76-81

ISBN: 978-989-758-014-7

 2014 SCITEPRESS (Science and Technology Publications, Lda.)

by a phenomenon called “cybersickness” (LaViola

Jr 2000), reducing significantly the user comfort and

his efficiency to perform a specific task in a virtual

environment. This observation is emphasized in the

context of interactive molecular simulations where

users manipulate the 3D structures during a

simulation in progress (Dreher et al., 2013).

Consequently, the need for alternative ways to

navigate in virtual environments has been

emphasized by Hanson et al. (Hanson et al., 1997)

who cited several families of navigation paradigms

increasing significantly the experience of the users.

Based on these different observations, we propose in

this study to bring new navigation paradigms aiming

to fill the gap between virtual and immersive

environments and molecular visualization. To do so,

we took into account the importance of geometry in

structural biology. Indeed, it has already been shown

that most of large 3D structures were constructed

around specific symmetry layouts (Goodsell and

Olson, 2000). Symmetry is not only a spatial feature

of these molecular complexes but also plays a

significant role on the stability and then the function

of such complexes. Our algorithm take as input the

symmetry of a multimeric complex and the

geometrical transformation between each monomers.

This symmetry can be manually set up or

automatically approximated using principal

component analysis to detect the main orientations

of monomers or by specific software dedicated to

this analysis (Kim et al., 2010). Such information are

good enough to provide a spatial basis to orient the

virtual world of exploration. Through the symmetric

nature of molecular complexes and by identifying

the tasks a scientist would have to perform in

molecular exploration, we will setup several

navigation paradigms aiming to improve the user

experience and efficiency.

2 CONTENT FORMALISATION

IN STRUCTURAL BIOLOGY

Development of camera models has to take into

account both the constraints linked to the

visualization in immersive conditions and the

navigation possibilities extractable from the

molecular complexes of interest.

The notion of symmetry is of first importance in

structural biology. As soon as a complex is formed

of more than two identical chains, a symmetric

configuration has significant chances to intervene in

the structuration of the monomers. These particular

layouts, found in large molecular complexes, play a

crucial role in most of the biological functions

accomplished by these structures. They are involved

in complexes stability but sometimes also in the

primary function of the complex itself. Many

transmembrane proteins present a pore where ions

will pass through to reach the inner or outer part of a

cell. Most of the times, this pore will be also the

exact symmetry axis of the protein. Each monomer

of the complex will present a symmetric

transformation to fit another monomer. Several types

of symmetries can be found among molecular

complexes and we listed some of them in the Figure

1. Each of them can be used as a base for a

navigation system since they provide a first step to

orient the complex. Any orientation of an abstract

element in a virtual scene brings a new spatial

landmark for the user and allows reducing the

discomfort that could appear when dealing with such

large and non-oriented structures.

Figure 1: Several types of symmetries found in molecular

complexes. (A) GLIC, transmembrane protein composed

of 5 components with a single symmetry axis. On the left,

top view of the protein, on the right, transversal view. (B)

Virus capsid with two types of components presenting a

symmetry center overlaying the gravity center of the virus.

like symmetry.

We already cited the axial symmetry and it is one

of the most represented symmetry among large

molecular complexes. The ensemble of monomers is

often organized in a circle manner around the

symmetry axis that is coincident with the pore of the

protein (Figure 1A).

Viruses present an important number of different

symmetries, most of them central but for which

angles and distances of rotation are very variable

Content-guidedNavigationinMultimericMolecularComplexes

and bring an important list of possible structures

(Figure 1B).

Molecular complexes presenting important

structural roles in the cell often adopt symmetries

called “helical” (Figure 1C). The transformation to

pass from one monomer can be associated to a

screw-like movement. We can take the example of

microtubules that are constituted of hundreds of

subunits called tubulin and arranged with each other

in a helical way. Microtubules are part of the cell

skeleton and are involved in maintaining structure of

the cell.

Despite their importance in the cell and the

numerous functions that we just cited in a non-

exhaustive manner, very few algorithms are

dedicated to the identification of symmetry axes or

centre in molecular complexes. Among them, only

SymD (Kim et al., 2010) is available online and can

be applied on a structural complex coming from a

PDB structure. SymD is based on a fitting and

permutation of monomers algorithm to identify the

symmetries. In spite of its relative efficiency, SymD

cannot deal with structures of more than 10 000

atoms and then misses most of the large complexes

with the most remarkable symmetries. Moreover, the

program outputs only symmetry axes when we saw

that several structures present central ones.

Symmetries being the starting point for the

conception of navigation guides that will be

described, the automatic detection of these

geometric features have been developed by the team

but will not enter in the scope of this study.

3 USERS NEEDS IN

STRUCTURAL BIOLOGY

3.1 Context Support

Visualisation of molecular complexes has been

brought to everyone’s hands thanks to numerous

programs like PyMol (DeLano, 2002) or VMD

(Humphrey et al. 1996). In order to assess our

navigation paradigms we chose to develop, in a first

step, a PyMol plugin based on python language and

using the API available for this program. Our choice

to use PyMol comes from the fact that PyMol is

recognized to be broadly used software in the

structural biology community and could be then well

evaluated by scientists of the field. Our

developments are, however, completely independent

of the visualization software used and we expect to

port the paradigm on a large-scale visualization

platform very soon. A short-term use case will see

the integration of our paradigm in the specific and

emergent case of visual analytics. This development

will take place in an immersive context represented

by a CAVE-like system. Together, the immersion

and visual analytics bring in the limelight the need

for proper algorithms addressing specific

navigations tasks that we listed in a non-exhaustive

way in the following section.

3.2 Navigation Tasks

The first steps of complex visualisation take place

through the external exploration of the overall shape.

These steps require a distant position of the camera

as well as a specific orientation of the complex for

the user. This orientation will be fixed during the

whole exploring process and any movements of the

camera will be made to avoid to the user to lose this

orientation setup with respect to the complex.

It is really difficult to visualise a specific region,

repeated along the different monomers of a complex.

Navigation without constraints makes the quick and

uniform observation of these regions almost

impossible. The movements to reach these regions

involve quick and precise motions to be performed

in order to simultaneously keep some spatial

landmarks and find the good point of view in the

middle of thousands of particles. The feeling to jump

from one monomer to the other in a smooth and

quite instantaneous way is particularly interesting in

the aim to compare binding sites or dynamic

structures involved in complexes stability. Selection

of similar and repeated regions of complex

monomers allows the extraction of atoms as graphic

objects used to perform certain standard geometrical

analyses like Root Mean Square Deviation (RMSD)

calculation. Several other comparisons like the

number of bonds among a region or the size of

binding pockets accessible for external links are also

elements used to study a complex. In the same state

of mind, distance between atoms or group of atoms

is indispensable when coming to protein studies.

On top of the sequential navigation along the

monomer, we cannot dissociate the importance of

the point of view a user will have to analyse the

region of interest. This is particularly true in the case

of regions completely embedded and hardly

accessible in the structure. We can then add an

algorithm to compute the best point of view from a

user position toward an interesting region.

As we already evoked, few molecular structures

present unique internal arrangements that participate

to their function. These functions are mainly

BIOIMAGING2014-InternationalConferenceonBioimaging

functions of passage where molecules of water or

ions are exchanged between the inside and the

outside of a cell membrane. This is made possible by

the presence of a pore that also plays the role of the

symmetry axis around which the different monomers

constituting the transmembrane protein stand. Pores

are then particular structural arrangements where

many biological events can take place and of a first

importance for scientists. They are really interesting

to visualize but not so easy to reach and follow

because of their burying state. We setup the

possibility to easily anchor the camera to the

entrance or exit of these biological “corridors” to let

the user explore them via specific navigation paths.

Proteins are structured in tertiary structures that

obey to specific rules, well known and identified for

several years. It is sometimes useful to explore these

geometrical patterns to value the shape and stability

of the proteins. We chose to use the metaphor of the

rollercoaster to minimize the interaction with the

user. In this setup, the user only controls the

movement speed and direction (forward or

backward) but neither the path nor the orientation.

4 CAMERA MODEL

Our model of camera must address the different

needs listed above in order to be pertinent for the

scientists. It will be done through but putatively

coupled navigation modes that we will describe

now.

4.1 Navigation Modes

When a centre or axis of symmetry is detected, the

molecular system is re-oriented to have its symmetry

axis merged with the axis {0, 1, 0} of the {x, y, z}

orthonormal reference. A translation is also applied

to merge the basis of the complex with the origin of

the coordinates system.

In a first mode of navigation that we could call

“simple exploration”, the camera is oriented in a

way that it always faces either the centre of

symmetry or the centre of the symmetry axis when it

is located at the complex level (Figure 2, area B). In

the external areas (Figure 2, areas A), camera up

follows the global vector model (Khan et al., 2005)

that keeps it fixed parallel to the symmetry axis if

existing or fixed in a way to keep the user head at

the same orientation with respect to the molecular

system. Movements along the 3 dimensions are

made in the same way, via the interaction with a

unique button associated to each direction {x, y, z}.

A translation along the camera forward will have a

“zoom-in”/”zoom-out” effect.

Figure 2: Schematic view of navigation paths and camera

orientations with a symmetry axis (purple). The molecular

complex is coloured in orange, areas A are outside the

structure whereas area B encompasses the ensemble of the

structure along the y axis. Each example of a camera

position is associated to a number from 1 to 5. The camera

forward is in green and the camera up in black.

A right translation will perform a turn around the

structure while keeping the same distance between

the camera and the symmetry centre. Finally the user

will have the possibility to go up and down along an

axis parallel to the symmetry axis in area B (Figure

2, position 1) but will fly over the top or base of the

complex when in areas A (Figure 2, position 2).

During the hovering of one of the complex

extremity, the camera forward will be focus on the

closest complex extremity.

At the intersection between the hovering

trajectory and a symmetry axis, a new mode of

navigation can be activated and will give the

possibility to navigation along the symmetry axis

(Figure 2, position 3). In this mode, the camera up

will be kept in the same direction that it was when

the user was flying over the structure to avoid any

navigation issues in terms of orientation losses.

When the user is inside the complex, along the

symmetry axis, we let the possibility to change the

navigation mode for a free 360-turn around a

specific position (Figure 2, position 5). In this mode,

the camera forward will not be confounded with the

symmetry axis anymore but will be perpendicular to

it. The camera up will be along the axis and the user

will have the possibility to look in every direction

from his position. The movement might be

associated to the one of a panoramic elevator

Content-guidedNavigationinMultimericMolecularComplexes

allowing the exploration of the internal structure of a

protein.

To answer the basic needs of the field experts,

the possibility to target a specific region of a

monomer can be split into 4 successive steps:

1. Constrained navigation as illustrated in

Figure 2 to face the interesting region.

2. Selection of the interesting area and best

point of view computing.

3. Memorisation of the point-of-view

information in terms of camera parameters.

4. Jump to the following monomer thanks to

the symmetry information.

4.2 Accessibility Computing

The previous navigation mode includes a research of

an optimal point-of-view relative to an interesting

area pointed by the user. This algorithm operates in

the following way: Starting with the center of an

area identified by the user, a sphere is created

around this point with a radius matching a

configurable distance between the camera and the

target. From each element of the sphere surface, a

ray is cast toward the target. If a ray crosses a cell of

the grid with an atom in it, the grid element

corresponding to a surface starting point is

considered as occulted.

Figure 3: Grid splitting of the region surrounding an atom

of interest (green). Each neighbouring atom (red)

constitutes an occlusion for the camera view. The optimal

point-of-view cones are represented in blue.

At the end, each element of the surface is

associated to a 2D table and we extract the area with

less occulted neighbors (Figure 3). The centers of

these areas, once re-transformed into 3D

coordinates, yield the observation points with the

least occlusions to observe the target. The user is

then able to choose among the optimal points of

view calculated by modifying the position and the

orientation of the camera.

This accessibility grid can also be used to follow

the shape of protein surfaces or membranes. In this

mode, the camera up is aligned on the surface

normal and any movement can be associated to

navigation on a ground where the user is limited to 2

dimensions control with a freedom degree of

rotation around the camera up axis.

4.3 Structures Manipulation

The algorithm of optimal point-of-view reaches

some limits when we come to protein areas

completely buried into the structure or at the

interface of two monomers. In these situations,

accessibility is null and there is no simple algorithm

to visualize these regions. Based on this observation,

we went further in the use of the symmetric layout

found in molecular structures. In order to put into

light hardly accessible regions, we decided to

change the 3D structure of our proteins. The user is

able to control the 3D modification to fit his wishes.

Some translational movements are applied to each

monomer in order to further them from each other

and then free several regions that were previously

hidden in the structure (Figure 4). By a simple

interaction with a button or by letting the program

computes the movement automatically according to

the camera position we can move the monomers

away along an axis starting from the symmetry

centre/axis to the monomer centre of mass.

Figure 4: Top view of GLIC protein. (A) Default layout of

the different monomers. (B) Spreading of the different

monomers by translation with respect to a vector linking

the symmetry axis centre to each monomer centre of mass.

BIOIMAGING2014-InternationalConferenceonBioimaging

5 CONCLUSIONS

Immersion for molecular exploration brings an

interesting dimension for the study of certain

biological events. However, it also brings some

navigation issues that can be easily extended to

desktop environments. Without any specific

navigation paradigm, the exploration of abstract and

scientific data can easily lead to significant spatial

landmarks losses and then decrease the user

experience and efficiency. To tackle this problem,

navigation guides can be quickly setup. They are

based on the most common feature that most of

molecular complexes of a certain size share, a

symmetric layout geometrically connecting the

monomers between them. But beyond the simple

comfort of the user, if correctly implemented, the

constraints extracted from any centre or axis of

symmetry can also become useful helps for the

execution of daily standard tasks in structural

biology.

Next steps will be the evaluation of our paradigm

by structural biology experts. We will base our

assessments on the broadly accepted evaluation

benchmark proposed by Bowman et al (Bowman et

al., 1997). The criteria used to assess the navigation

paradigms group, in a non-exhaustive way: the task

execution speed, its accuracy, the user spatial

awareness in the virtual scene during and after the

experience, the comfort of the user, etc…

It is important to notice that our paradigms are

completely independent of the navigation technic or

the visualisation system used. Indeed, they can be

applied from immersive environments like CAVE

systems to desktop ones and with mouse/keyboard

as well as 3D mice or tracking solutions (Chen et al.,

2013). A navigation control can easily be substituted

to one other while keeping a behaviour consistency

of the camera defined in function of the scene

content.

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Content-guidedNavigationinMultimericMolecularComplexes