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©2016 THE BIOPHYSICAL SOCIETY OF JAPAN
Biophysics and Physicobiology
https://www.jstage.jst.go.jp/browse/biophysico/
Regular Article
Special Issue
“Protein-Ligand Interactions”
◄ Significance ►
Vol. 13, pp. 97–103 (2016)
doi: 10.2142/biophysico.13.0_97
Corresponding authors: Laycock Stephen and Hayward Steven, School
of Computing Sciences, University of East Anglia, Norwich, NR4 7TJ
United Kingdom.
e-mail: s.laycock@uea.ac.uk; sjh@cmp.uea.ac.uk
Determination of locked interfaces in biomolecular complexes
using Haptimol_RD
Georgios Iakovou1, Stephen Laycock1 and Steven Hayward1
1School of Computing Sciences, University of East Anglia, Norwich, UK
Received December 25, 2015; accepted February 26, 2016
Interactive haptics-assisted docking provides a virtual
environment for the study of molecular complex forma-
tion. It enables the user to interact with the virtual mole-
cules, experience the interaction forces via their sense of
touch, and gain insights about the docking process itself.
Here we use a recently developed haptics software tool,
Haptimol_RD, for the rigid docking of protein subunits
to form complexes. Dimers, both homo and hetero, are
loaded into the software with their subunits separated in
space for the purpose of assessing whether they can be
brought back into the correct docking pose via rigid-body
movements. Four dimers were classied into two types:
two with an interwinding subunit interface and two with
a non-interwinding subunit interface. It was found that
the two with an interwinding interface could not be
docked whereas the two with the non-interwinding inter-
face could be. For the two that could be docked a “suck-
ing” effect could be felt on the haptic device when the
correct binding pose was approached which is associated
with a minimum in the interaction energy. It is clear that
for those that could not be docked, the conformation of
one or both of the subunits must change upon docking.
This leads to the steric-based concept of a locked or non-
locked interface. Non-locked interfaces have shapes that
allow the subunits to come together or come apart with-
out the necessity of intra-subunit conformational change,
whereas locked interfaces require a conformational change
within one or both subunits for them to be able to come
apart.
Key words: haptic feedback, force feedback,
protein docking, protein-protein interactions,
interwinding interface
The study of protein-ligand interactions has been and still
is an exciting research topic, with important applications in
drug design and protein-protein recognition. In nature, mol-
ecules interact and bind with other molecules to form com-
plex structures that control various regulatory and metabolic
processes of the living cell. In pharmacology for example,
drug behaviour (i.e. the therapeutic action and side effects of
a drug) depends closely on where and how the drug binds to
a given protein [1]. Cellular signalling, gene regulation, and
immunity are other examples of biological function that is
controlled by these interactions [2]. For several decades
researchers have been trying to study and replicate these
interactions in silico, using various computational models
and methods, often referred as to molecular docking.
Generally speaking, molecular docking describes those
methods that attempt to orientate and bind a ligand to the
active site of a protein by exploring an enormous number of
Recently we have developed a software tool, Haptimol_RD, which allows the user to control a ligand molecule via a
haptic device and feel its interactions with a receptor molecule. Here we have used Haptimol_RD on two types of
dimers, those with an interwinding subunit interface and those without a non-interwinding subunit interface. The
results show that for the interwinding dimers one or both the subunits much change conformation upon complex
formation whereas for the non-interwinding dimers this is not necessary. This leads to a new concept relating to
steric interactions between subunits; that of a “locked” interface.
98 Biophysics and Physicobiology Vol. 13
network model [23], and for steering molecular dynamics
simulations [24].
The majority of existing haptics-assisted docking systems
treat the molecules as rigid and account only for the van der
Waals and electrostatic interactions, unlike the automated
docking systems which often model molecular exibility to
some extent. These limitations stem from the fact that
modern haptic technology necessitates force refresh rates of
500 to 1000
Hz for high delity smooth and stable force
feedback [25–27]. When this rate is not met, the user experi-
ences device jittering and force discontinuities that limit
the usefulness of such a system. To address this strict time
constraint therefore, existing interactive docking systems
rely on various model simplications (e.g. model rigidity
and nonbonded interactions only), and processing-time-
acceleration techniques (e.g. precomputed force-grids)
[8,9,14,15,28–30]. They also limit the size of molecules they
can support to small biomolecules [11]. This is true also for
the few interactive systems that have attempted to model
molecular exibility, but failed to satisfy the 2ms time con-
straint of haptics [31,32]. As it stands, none of the existing
interactive docking systems can facilitate the docking of
large biomolecules, and as such they cannot help scientists
study and gain insights into the mechanisms of protein-
protein interactions.
We have recently developed a system for interactive
haptics- based rigid molecular docking that is able to handle
large biomolecules. Our purpose here is to report on the rigid
docking of proteins and ascertain whether there is anything
we can learn about the process of docking when the proteins
are able to undergo conformational change. It is clear that
when two molecules associate there will be to a greater or
lesser extent some degree of conformational change. Indeed
in some cases, this conformational change can be dramatic
as exemplied by examples of structures solved in the pres-
ence and absence of their binding partner, e.g. epidermal
growth factor and epidermal growth factor receptor. It is
clear that in such cases the rigid docking of the proteins in
the free state will not result in a favourable binding pose.
What though would we learn if we were to try to rigidly
dock proteins each in the conformation of the bound state?
One unknown is whether the correct binding pose can actu-
ally be achieved through rigid docking alone. If it cannot
then it shows that conformational change must occur in the
process of binding. If, however, the correct binding pose can
be achieved, it would imply that conformational change need
not occur although it certainly does not preclude the possi-
bility that it has. The main aim of the research presented
here, then, is to test whether the correct binding pose can be
achieved with rigid docking using selected examples, and if
it cannot to conclude that conformational change must have
occurred in one or both of the proteins during the binding
process. The examples we have selected come from a dataset
created by Yura and Hayward [33]. This set of bound state
proteins, both homo-oligomers and hetero-oligomers, were
potential binding conformations and selecting the most
probable one. To achieve this, automated docking [3–5]
approaches utilize efcient search strategies and scoring func-
tions in order to explore the protein/ligand conformational
space, evaluate potential binding poses, and score/select
the most favourable of those poses. Their execution relies
only on computing power, and they can search for and pro-
vide probable binding conformations for a large number of
protein- ligand targets, e.g. for the virtual screening of drugs
[6]. Even though automated methods are the most popular in
the eld, they often produce incorrect results [7]. Moreover
by design, they do not allow human intervention in the dock-
ing process, and as such cannot benet from human knowl-
edge, and expertise. Interactive docking addresses these
issues by allowing rational human thought, intuition and
experience to execute the pose sampling and selection pro-
cess. In interactive docking, the user is able to see and move
the virtual molecules in real time, and perform a knowledge-
guided search and selection of the nal binding pose. Inter-
active docking systems often combine 3D molecular visual-
ization with haptic technology as a means to enhance user
experience with the sense of touch. Haptics-assisted docking
systems provide an immersive virtual docking environment
where the user can interact with the molecules, sense the
interaction forces, and utilize this visuohaptic feedback to
identify and select the right binding conformation [8,9].
They are also useful learning tools for the study of protein-
ligand interactions during docking, and research tools for
forming and investigating new ideas and hypotheses perti-
nent to complex formation (e.g. the effects of a mutation)
[10]. Unlike automated approaches, haptics-assisted ap-
proaches cannot facilitate the docking of a large number of
different protein-ligand targets within a session, due to their
interactive nature. However, they allow the user to intervene
cognitively in the docking process, and as such can assist
experts to improve upon the docking conformation produced
by their automated counterparts [9–11].
The benets of haptic technology in molecular docking
were rst studied by Brooks et al. with the GROPE III
project [12]. Their system utilized a modied Argonne E-3
Remote Manipulator (ARM) for ligand movement and force
feedback display, and managed to accelerate the docking of
small rigid molecules by a factor of two. Subsequent works
investigated the benets of haptics in computer-aided drug
design [13], in rational drug design [14], in computer-aided
molecular design [15], for the study of protein-drug and
protein- protein interactions [9,16,17], and in e-learning and
education [18–21]. These studies indicated that haptics-
assisted docking can help users’ (experts or students of struc-
tural biol ogy) learn about the process of molecular binding,
and experts to improve upon docking conformations that
have not been (or could not be) veried experimentally. In
addition to docking, haptic technology has also been used
for exploring the solvent accessible surface (ISAS) of a bio-
molecule [22], deforming protein structure using an elastic
Iakovou et al.: Haptimol_RD: locked interfaces in protein complexes 99
interaction forces on the haptic device, the values were con-
verted from kJ
mol–1
nm–1 to Newtons and then scaled by a
constant factor. Similarly to Iakovou et al., we converted the
initial force to Newtons by dividing by 6.02329×1011 (since
1N is equivalent to 6.02329×1011
kJ
mol–1
nm–1), and then
scale it by 109 to obtain a good range of haptic forces.
Homodimers and Heterodimers Investigated
In this study we attempt to dock rigidly the subunits of
known homodimer and heterodimer proteins. Four known
dimer proteins were selected for this purpose; namely, the
two heterodimer proteins Nitrile Hydratase and C-
Phycocyanin, and the two homodimer proteins Aspartate
Aminotransferase and Aspartate Racemase as dened in the
PDB les 1AHJ, 1I7Y, 1AHE, and 1JFL, respectively (Table
1). The proteins were selected from the Yura and Hayward
[33] dataset based on their SF values. Yura and Hayward
utilized this dataset in order to study the interwinding nature
of protein-protein interfaces, and discovered that subunits
with SF < 1.25 do not have interwinding interfaces, whereas
subunits with SF > 2.0 have interfaces that interwind exten-
sively. The protein-protein interface in the former case is
classied as at-against-at, whereas the interface in the
latter case is classied as interwinding. For those subunits
with a at-against-at interface, we expect to be able to dock
them rigidly, since no major structural deformations are
classied as having interwinding or at-against-at inter-
faces using a measure termed the Surroundedness Factor,
SF. SF is 0 for a perfectly at interface but rises to values
greater than 2.0 for interwinding interfaces. Our selected
examples are from those classied as at-against-at and
inter winding.
Methods
Haptimol_RD
Haptimol_RD is an interactive application that can facili-
tate the haptics-assisted docking of large rigid biomolecules
(Fig. 1). It is designed to run on consumer level hardware,
(i.e. there is no need for specialized/proprietary hardware),
and utilize a relatively inexpensive haptic device, i.e. 3DOF
Geomagic Touch. The application is written in Visual C++,
and uses the OpenGL library for 3D graphics rendering. It
can compute the nonbonded interaction forces, in real time,
either on the CPU or the GPU, using the cut-off-based force
calculation methods proposed by Iakovou et al. [34,35].
Both methods compute the forces using the set of inter-
atomic interactions within a given cut-off distance, and uti-
lize efcient proximity querying algorithms (optimized for
CPU and GPU execution) in order to identify this set. Force
computations on the GPU are executed using OpenCL.
During a docking simulation, the user can switch on/off the
electrostatic and VDW forces in order to investigate their
effects. Haptimol_RD renders a molecular structure using
space-lling and the Cα-backbone models, and depicts a
force by an arrow. At any point and time during the simula-
tion, the user can save a given conformation in a PDB le
and use it for further investigation. Using Haptimol_RD, we
attempted to rigidly dock subunits of heterodimer and homo-
dimer proteins solved in the complexed state.
Force Model
The interactions included were van der Waal (VDW) and
electrostatic. The VDW was modelled using the 12-6
Lennard- Jones (LJ) potential, and the electrostatic using
Coulomb’s law. The non-bonded LJ and Coulombic param-
eters were obtained from the Gromos54a7 [36] force eld
using the pdb2gmx tool provided by Gromacs version 4.6.2
[37]. All energy/force computations were performed on the
GPU using a cut-off distance of 8
Å. To render the resultant
Figure 1
Ligand (purple) interacts with receptor within Haptimol_
RD. The green arrow indicates that the user is sensing weak repulsive
forces on the haptic device.
Table 1
The two heterodimer and homodimer proteins used in the interactive rigid docking experiments studied here
Name PDB Code Type # of Residues
in Subunit A
# of Residues
in Subunit B SF
Nitrile Hydratase 1AHJ Heterodimer 198 212 2.11
C-Phycocyanin 1I7Y Heterodimer 162 172 0.87
Aspartate Aminotransferase 1AHE Homodimer 396 396 2.84
Aspartate Racemase 1JFL Homodimer 228 228 0.78
The subunits of dimers with an SF value less than 1.25 are expected to interface rigidly, whereas the subunits of dimers with an SF
value greater than 2.0 are expected to undergo substantial conformational change during docking.
100 Biophysics and Physicobiology Vol. 13
ligand PDBs prior to invoking pdb2gmx. In these simula-
tions the ligand was attached virtually to the haptic device,
whereas the receptor was set xed in space. Using the 3D
structure of the original complex as a visual guide, we moved
the ligand around the receptor with the haptic device, ex-
plored the receptor’s surface, sensed the interaction forces,
and attempted to guide the ligand back to its binding pose
(Fig. 2). We executed each simulation for several minutes, in
order to experiment with different docking conformations,
and investigate visually (i.e. by displaying the energy) and
haptically the respective energy and force landscapes. We
also recorded the energy value at each haptic frame. Figure
3 shows the energy trajectories and backbone RMSD trajec-
tories between the ligand position during interactive docking
and the ligand position in the experimental structure when
both receptor structures are superposed. As can be seen for
C-Phycocyanin (Fig. 3(a)) and Aspartate Racemase (Fig.
3(b)) docking succeeded in reproducing the experimentally
determined pose, whereas for Aspartate Aminotransferase
(Fig. 3(c)) and Nitrile Hydratase (Fig. 3(d)) the experi mental
pose could not be achieved.
Our results reveal two interesting points. The rst is the
existence of a “sucking effect” on the haptic device as we
approached the correct binding pose that coincided with
the sudden drop in energy. In order to conrm this we per-
formed a further four independent docking experiments on
C- Phycocyanin and Aspartate Racemase. The results are
shown in Figure 4 and in each experiment the sucking effect
was felt on the haptic device as the correct binding pose was
achieved and the energy dropped. The other nding is that in
some cases the true binding pose can be achieved using rigid
docking whilst for others it cannot, and that this relates to the
nature of the interface as classied by its SF value, i.e. at-
against-at or interwinding. For example, in aspartate amino-
transferase the N-terminal regions prevent docking (see Fig.
5). It is probable that these regions are exible for the two
subunits to be able to bind.
antici pated during docking. By contrast, rigid docking is not
expected to work for those subunits with an interwinding
interface, since they would be expected to undergo substan-
tial conformational changes upon binding.
Results
Using Haptimol_RD and the dimers of Table 1, we exe-
cuted interactive docking simulations in an attempt to dock
rigidly the subunits forming those dimers. The purpose of
these simulations was threefold: (a) to examine whether or
not it is possible to obtain the correct binding conformation
using an interactive haptics-assisted rigid-docking appli-
cation, b) to relate rigid-docking success or otherwise to
structure- related indicators such as the SF value, and c) to
devise a test that could easily identify which molecules
have to undergo conformational changes during docking. All
inter active docking simulations were executed on a 2.93
GHz
Intel Core i7 PC running under a 64
bit version of Windows
7 with an NVIDIA GTX580 GPU. The PC was equipped
with 8
GB RAM, the GPU with 1.5
GB RAM, and we uti-
lized the 3DOF Geomagic Touch haptic device, formerly
known as the Phantom Omni from SensAble Technologies
(Fig. 2).
To obtain the receptor and ligand molecules for each
simulation, we used the initial PDB le, and separated the
two subunits described within into different PDB les, thus
producing eight new PDB les in total. For the purpose of
these simulations we assigned subunit A as the receptor, and
subunit B as the ligand. To add the necessary hydrogen
atoms and obtain the values for the nonbonded terms of the
Gromos54a7 force eld (and the respective topology les),
we used Gromacs’ pdb2gmx tool as follows,
pdb2gmx -f xxxx.pdb -o gmx xxxx.pdb -p gmx xxxx.top
-ff gromos54a7 -ignh -water none -merge all
where xxxx is the molecule’s pdb code (see Gromacs man-
ual [37] for more information). We also deleted all heterogen
atom coordinates (e.g. water) listed within the receptor and
Figure 2
Left: The docking of chain A (grey carbon atoms) and B (purple carbon atoms) of homodimer protein Aspartate Racemase (1JFL)
using Haptimol_RD and the 3DOF Geomagic Touch haptic device. Using the haptic device the user guides, orientates and docks chain B to chain
A, while sensing the interaction forces on the haptic device. Right: A close-up view of the same docking simulation.
Iakovou et al.: Haptimol_RD: locked interfaces in protein complexes 101
to the docking of molecular structures solved in the bound
state. X-ray renement methods use force-elds that are
also used in Molecular Dynamics simulations such as the
Gromos54a7 force-eld used here for the non-bonded inter-
actions between the two subunits. Although in X-ray rene-
ment the “energy” contains terms which include structure-
factors from the X-ray experiment, given the overwhelming
contribution of the Lennard-Jones repulsive terms when
atoms overlap, it is perhaps not surprising to nd that the
docked structure is at an energy minimum when the experi-
mental terms are omitted. This explains the “sucking effect”
felt on the haptic device, which pulls the ligand into the
correct pose when one gets close to the experimentally deter-
mined conformation (<5
Å RMSD) and is not felt for incor-
rect binding poses. Our results using complexes that have
interwinding and non-interwinding interfaces suggest that
conformational change must occur upon binding for those
with an interwinding interface as determined by its SF value.
Conversely, those tested with a non-interwinding interface
Discussion and Conclusion
Haptics assisted docking software allows the user to learn
about the docking process and the interactions involved.
Although there is a long history of the use of haptics in bio-
molecular docking, until now these methods have been
applied to the docking of small molecules or a small molecule
to a protein as in drug development applications. Advanced
spatial decomposition methods, particularly in conjunction
with the parallel processing capabilities of the modern GPU,
has enabled the development of Haptimol_RD, a software
tool for the docking of large biomolecules. Here, using
Haptimol_RD, we have, for the rst time, been able to study
the interaction of two large protein subunits as they come
together to form a larger complex. Haptimol_RD does not
model protein exibility and this study is therefore neces-
sarily restricted to rigid docking. As rigid docking would not
be expected to be able to dock molecules that have been
solved separately in the free state, this study has been limited
Figure 3
Trajectories of the interaction energy (black lines) and the backbone RMSD between the ligand position during docking and the ligand
position in the experimental structure (red dots) obtained during the interactive docking of: (a) the α and β subunits of the heterodimeric protein
C-Phycocyanin (1I7Y); (b) the two subunits of the homodimeric protein Aspartate Racemase (1JFL); (c) the two subunits of the homodimeric
protein Aspartate Aminotransferase (1AHE); (d) the α and β subunits of the heterodimeric protein Nitrile Hydratase (1AHJ). We were able to dock
the subunits in (a) and (b), but not in (c) and (d).
102 Biophysics and Physicobiology Vol. 13
can imagine other kinds of interfaces where the two subunits
are locked, e.g. where a domain movement has enclosed part
or all of the other subunit. It could also involve only inter-
locking side chains although further investigations will need
to be carried out to conrm this. This locked and non-locked
concept relates to steric interactions and not to softer inter-
actions such as electrostatic interactions. It relates therefore
to the shape of the interface.
Although rigid docking has obvious limitations we have
shown here that it can be used to reveal features of protein
complexes that would be difcult to determine by other
means.
A video showing the docking of C-Phycocyanin is avail-
able through the following link: http://www.haptimol.co.uk/
movies/iakovouetal.mp4.
Haptimol_RD will be released before the end of 2016.
Author Contribution
SH and SL conceived the experiment, GI carried out the
simulations and all authors contributed to writing the manu-
script.
Acknowledgments
We acknowledge colleagues that have been supporters of
our work on biomolecular haptics.
Conict of Interest
There is no conict of interest related to this work.
could be docked correctly suggesting that conformational
change need not occur upon binding. It is clear that one
could generalise these results beyond interwinding and non-
interwinding interfaces to a new concept, namely locked and
non-locked interfaces. A non-locked interface is one where
no change in internal conformation is necessary to bring the
subunits into their correct pose or to take them apart. By
contrast a locked interface is one where the two subunits
cannot be brought into the correct binding pose or be taken
apart without a change in internal conformation of at least
one of them. For a truly interwinding interface this confor-
mational change may involve a folding type process but one
Figure 4
Trajectories of the interaction energies obtained during
four independent (shown in black, red, blue and green) docking exper-
iments on: (a) the α and β subunits of the heterodimeric protein C-
Phycocyanin (1I7Y); (b) the two subunits of the homodimeric protein
Aspartate Racemase (1JFL). The graphs display only the last 25 sec-
onds from each simulation for clarity purposes. The experimental
docking pose could be achieved for each of the trials and attainment of
the experimental docking pose was associated with a dramatic drop in
the interaction energy. This drop in energy coincided with the sucking
effect felt on the haptic device.
Figure 5
Left: Chain A and chain B of the homodimer Aspartate
Aminotransferase (1AHE) in closest docking conformation using
Haptimol_RD. The N-terminal regions prevent the two subunits from
achieving the correct docking pose. Right: The X-ray structure of the
homodimer.
Iakovou et al.: Haptimol_RD: locked interfaces in protein complexes 103
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