Simbios DBP and Seed Project recruitment: Process and Content
Simbios executive committee
Russ Altman, PI
(russ.altman@stanford.edu)
Scott Delp, Co-PI (delp@stanford.edu)
Jeanette Schmidt,
Exec. Director (Jeanette.Schmidt@stanford.edu)
Peter Lyster, NIH Program Officer (lysterpe@nigms.nih.gov)
Jennie Larkin, NIH
Lead Scientific Officer (larkinj2@nhlbi.nih.gov)
Process and
Schedule
Simbios was recruiting new Driving
Biological Problems (DBPs) to start in the fall of
2007. Applications were due
October
30th 2007
. We were specifically looking for Driving Biological
Problems that are consistent and complement our core software development
activities. We are interested in expanding our core software components and
developing new application areas for existing software components, such as
applications that expand the use of our multi-body dynamics component, Simbody. Descriptions of current DBPs and examples of other funded seed projects are given in the appendices. We
were looking for DBPs based on NIH supported
research, as well as seed projects that may eventually evolve to DBPs.
Preference was to be given to projects that:
- address mesoscale modeling
–hence filling the scale gap between molecular modeling and the modeling
of organs, (see Appendix 1 for current DBPs).
- complement core software development activities and are
consistent with the physics-based modeling and simulation goals of Simbios.
- integrate
in a sensible way with systems biology and physics-based modeling
- address multiscale modeling
- have current NIH support for the underlying biology
(such as R01, P-grant, etc.)
Funding
For DBPs: up to 10% support for
the PI and 1 postdoc or software developer in support
of the project for 1 to 3 years.
For seed projects: 1 a student or postdoc for six months
Evaluation
A 1-5 page description of the proposed work containing a:
- brief
background of the research, including current NIH support,
- description
of the work to be performed (specific aims),
- description
of the software contributions to be made available on Simtk.org (growth in
the use of Simtk.org is a critical goal of Simbios),
- summary
of all personnel to be supported (or partially supported)
The Simbios Executive Committee
and the Simbios Lead Science Officer (Jennie Larkin)
and Program Officer (Peter Lyster) reviewed
submissions.
Distribution
1.
Posted on the Simbios website
2.
Direct mail to all Simbios collaborators – including
·
Simbios investigators
·
Active collaborators (R01, previous seed
projects).
·
Investigators that have approached Simbios with regards to a collaboration
3.
Simbios Science
Officers
4.
Simbios Science
Advisory Board Members
Examples of currently and previously funded DBPs in order of scale
RNA Dynamics
PIs: Dan Herschlag and Russ
Altman; NIH grant: P01 GM66275
Abbreviated version of Specific Aims:
Using the Tetrahymena ribozyme as a model, determine:
Aim 1: The
mechanism of its rapid electrostatic collapse at the onset of folding
Aim 2: The
spectrum of intermediates that are formed in folding and unfolding pathways
Aim 3: The
“landscape” for its folding, preferred pathways, features critical for the
choice of the pathways taken along this landscape under conditions that
approximate physiological.
Myosin Dynamics
PI: James Spudich; NIH Grant:
5R01GM033289-20
Abbreviated Specific Aims:
Use experiments and simulations to elucidate the mechanism
of energy transduction by the following myosin motors:
Aim 1: Myosin V: A
classical myosin, with strong evidence for a lever arm mechanism.
Aim 2: Myosin VI:
A non-classical myosin, which moves by an unknown mechanism.
Neuromuscular
Dynamics
PI: Scott Delp; NIH Grant:
R01 HD33929 and R01 HD 46814
Abbreviated Specific Aims:
Aim 1-3: Determine
if, and under what conditions, the following contribute to excessive knee flexion: 1)
Tight Hamstrings 2) Weak Hip Extensors or Weak Ankle Plantar Flexor
3) Tight Iliopsoas Muscles
Aim 4: Evaluate
the Capability of Dynamic Simulations to Identify Appropriate Treatments.
Cardiovascular
Dynamics
PIs: Christopher Zarins and Charles
Taylor; NIH grant: 1R01 HL64327
Abbreviated Specific Aims
Aim 1: Utilize 4D
MRI
analysis methods to characterize hemodynamic conditions and wall motion of the porcine and human thoracic and abdominal
aorta.
Aim 2: Apply
the cardiovascular dynamics methods to construct a virtual aorta.
Aim 3: Modify the
virtual aorta model to match the anatomic dimensions and wall thickness of the
aortas of the normal volunteers imaged in the companion R01 grant.
Examples of previously funded seed projects
PI: Darryl G. Thelen, Ph.D., University of Wisconsin-Madison
The Incorporation of Ground Contact Models When Simulating
Subject-Specific Gait
Background
Rehabilitation of persons with gait disorders is a
significant and challenging health concern. The challenge arises, in
part, because gait pathologies can have many sources, including
neurological injury, muscle weakness, and contractures. Current
motion analysis techniques, based on inverse dynamics, are often
insufficient to identify the cause of an individual’s pathology
(7). Forward dynamic simulation approaches overcome this limitation
by directly representing the causal relationship between muscle
excitations and movement (7). Furthermore, simulations can be used to
predict the consequences of interventions such as strengthening, functional
electrical stimulation and surgical treatment (1). In this work, we
seek to enhance the capability and availability of software tools for
simulating subject-specific gait, and for predicting the effects
of interventions on movement.
We have previously established a computationally efficient
approach, termed computed muscle control (
CMC
),
for generating muscle-actuated simulations of subject-specific motion (4, 5).
With
CMC
, complex simulations are generated
in minutes, which is two to three orders
of magnitude faster than conventional approaches. More importantly,
the simulations are extremely accurate with joint angles typically tracked
within one degree. We have successfully used
CMC
to
analyze the causes of gait disorders (2) and to characterize muscle mechanics
during running (6). However, a remaining shortcoming of our current
approach is the direct use of measured ground reaction force trajectories
in the forward simulation. While sufficient for studying small deviations
in movement, this approach is insufficient to simulate the deviations in
movement, which can occur after major interventions, such as orthopedic
surgery.
Description of Work to be performed
The goals of this work are to:
1) Develop an algorithm for identifying the parameters of a
ground contact model that replicate subject-specific ground reaction
forces.
2) Incorporate the contact identification algorithm into a
suite of software tools (uwpipeline) to be
maintained on Simtk.org for efficiently generating simulations of human
movement.
Details omitted
Software Contributions to be made to SimTK
Our algorithms will be coded in C and made compatible to
link with neuromusculoskeletal models created
using SIMM-Pipeline, which is the leading software package for
simulating human movement. Source code, executable programs, examples
and documentation will all be deposited in an open-source project (uwpipeline) on Simtk.org, so as to enhance the capability
of others to adopt and use the framework. These software packages
will also be compatible with OpenSim, since that
framework is designed to be backward compatible with SIMM-pipeline. The
eventual re-coding of the uwpipeline software as a
plug-in for OpenSim will likely be warranted as
the software matures and becomes useful to the community.
PI: Patrice Koehl, Computer Science and
Genome
Center
,
University
of
California
,
Davis
ElecTK: A Toolbox for
Macromolecular electrostatics
Specific Aims:
Develop and implement a new formalism for computing macromolecular
electrostatics.
We propose to use a generalized Poisson-Boltzmann-Langevin equation to describe the electrostatic
field generated by a macromolecule in water, based on a description of the
solvent and ions as an assembly of freely orienting dipoles. We will
develop an extensive computational toolbox for electrostatics calculations, ElecTK that will be incorporated into SimTK.
Background
Traditionally, the non-linear Poisson-Boltzmann equation (NLPBE) provides an accurate description of the electrostatics
field around a molecule (for a recent review, see Koehl,
2006). The NLPB formalism assumes continuum solvent, with a fixed
dielectric constant, as well as a bulk description of the ionic interactions
(using Debye-Huckel theory). While NLPBE is
used routinely to study electrostatic interactions in proteins,
its applications to nucleic acids are more limited, as these two
assumptions may then not be valid. Water is known to be organized in
at least a first layer around macromolecules (the “water sites” in the case of tRNA (Westhof, 1988), and
some ions are known to be immobilized at specific sites. There is
therefore a need for a new formalism for the computation of electrostatics
energy that includes the density of water dipoles as well as the density
of ions around a molecule as parameters. Electrostatics calculations
remain computationally intensive and difficult to set up, despite efforts to
develop web interfaces to facilitate the latter (see Koehl,
2006). There is therefore a need for a comprehensive toolkit for
computing macromolecular electrostatics that would be freely available, easy to
interface with other applications, and available as a web service to allow
non specialists to perform these types of calculation. The development of
such a toolkit is the central aim of this proposal.
Research Design
omitted
ElecTK: a toolkit for electrostatics
calculations. We will develop a toolkit for
computing macromolecular electrostatics that will include the fast PBE
solver and the GPBLE solver described above. This toolkit will include all
source codes required to implement these calculations in other programs, as
well as web services to provide access to these resources to non
specialists. ElecTK will be freely available
under SimTK, to ensure broadest possible use by
the biomedical community.
PIs: Robin Gutell and
Pengyu Ren
,
UT
Austin
Physical-based Coarse-Grain Modeling tool for RNA
Summary
We propose to develop a preliminary version of
physical-based coarse-grain RNA modeling program that will compliment Simbios’ effort in this area.
Background in Molecular Mechanical Model for
RNA Molecular mechanical simulations are used routinely to study
bimolecular structure and dynamics. At the core of molecular mechanics is
the empirical physical potential (force field) that provides the
quantitative description of molecular interactions. The current major
all-atom force fields for nucleic acids include AMBER and CHARMM. More and
more successes in nucleic acids modeling have been reported as the
force fields are constantly being improved and optimized [Cheatham, 2004; Mackerell, 204].
However, the current state-of-the-art of all-atom
simulations is limited to nanoseconds and a few hundred nucleotides,
whereas much of RNA dynamics occur on longer temporal and spacial scales. To overcome the time and size scale
barrier, coarse-grain (CG) models where atoms are lumped into one particle
have been actively sought after for modeling macromolecules.
Bead-on-spring models have been attempted recently on
DNA
double helix [Tepper, 2005]. Mergell et al. proposed a model for
DNA
where each
base-pair is represented by a Gay-Berne ellipsoid and the sugar phosphate
backbone is modeled by harmonic springs. Harvey and coworkers have been
utilizing coarse-grained molecular mechanics model with pseudo nucleotides
to construct low resolution RNA structure. Simpler models based on
experimental stacking free energy [Freier, 1986;
Turner, 1987] and Gaussian chain entropy have been applied to predict RNA pseudoknots [Isambert, 2000; Xayaphoummine,
2003].
In general there are two types of approaches available for
coarse-graining, referred to as knowledge- and physical-based. The former
begins with direct survey of existing molecular structures. The later
follows the physical interpretation of molecular interactions such as those
represented in the all-atom force fields. In principle, a physically
consistent model is more transferable; e.g. a RNA model can be applied
to RNA-protein systems without significant reparameterization.
Furthermore, models at various coarse-grain levels can be combined in a multiscale fashion to improve the computational
efficiency while retaining critical details. Previously, we have developed
point multipole based electrostatic framework for biopolymers
(polarizable protein force field AMOEBA). It is
our goal to extend this framework together with anisotropic vdW function
to build up a coarse-grained molecular mechanics model for RNA.
Research Plan
omitted
Software contribution to Simbios
With the seed grant support, we will provide an initial
version of physical-based coarse-grain RNA modeling program that will
compliment Simbios’ current effort in this area.
The program will consist of energy and force evaluation routines based on
the coarse-grained physical model and associated parameters. This routine
can be combined with SimTK molecular dynamics
engine NAST. We will also provide a primitive rigid-body MD engine. With
our internal structure manipulation program, visualization will be made
through SimTK’s ToRNADo program.
PI: Jill Higginson, University of Delaware
Simulation of post-stroke hemiparetic gait: 2d vs 3d
Overview
Stroke affects approximately 700,000 Americans each year and
is the leading cause of long-term adult disability. Post-stroke hemiparetic gait is complicated by impaired muscle
activation, which results in abnormal muscle coordination patterns and
asymmetric movements. An improved understanding of muscle function and
dysfunction will facilitate the design of appropriate therapeutic interventions
based on each patient’s needs. Through the use of
muscle-actuated forward dynamic simulation, we can assess the relationship
between muscle function and observed movement patterns to identify
limitations and areas for improvement. Thus, the objectives of this
short-term proposal are to generate subject-specific simulations of a range of
gait patterns from individuals with post-stroke hemiparesis,
compare the performance of two optimization algorithms, and identify any
differences between two- and three dimensional simulation results.
Specific Aims
1. Generate subject-specific simulations of up to 10
subjects who walk with a range of post-stroke hemiparetic gait abnormalities (e.g. foot drop, equinus, hip circumduction). We will study how muscle
excitation patterns are linked to observed function and how these differ
between individuals.
2. Compare performance of two optimization algorithms (
SPAN
and
CMC
) for 2d and 3d simulations with
a representative case study.
3. Identify differences in muscle function deduced from 2D
and 3D simulations for each walking pattern.
Background
According to the American Heart Association, 7.7 million
people are living with the effects of stroke and over 700,000 people will
experience a stroke or recurrence of a stroke annually. Because stroke
impairs walking function, it is a leading source of long-term adult
disability. Gait deviations following a stroke are multiple and
varied. Spatio-temporal abnormalities
include asymmetric stance and swing duration, step length, push-off forces and
decreased walking speed. Zajac asserts that the basic
principles of movement coordination remain unclear despite years of
collecting kinesiological data. Forward
dynamic simulation, in conjunction with experimental measurements and optimal
control theory, demonstrates promise at elucidating principles of muscle
coordination. Muscle-actuated forward dynamic simulation offers a
deterministic framework, which permits the identification of underlying muscle
impairments and investigation of resultant movement
abnormalities. Moreover, the potential effect of individual muscles on
movement patterns can be studied, and used to deduce beneficial compensatory
strategies and therapeutic interventions.
Simulation studies have been used previously to identify
unique and synergistic properties of the uniarticular and biarticular plantarflexors and other muscles during walking in healthy adults. Through investigation
of a muscle-actuated forward dynamic simulation of normal walking, Neptune
et al. (2001) found that soleus and gastrocnemius provide vertical support of the center
of mass (COM) during stance phase, soleus contributes
to forward acceleration of the trunk in pre-swing, and gastrocnemius generates pre-swing leg energy. Based on the same framework, Higginson (2005) developed a simulation of slow gait (0.3
m/s) in healthy adults to study the altered contributions of the plantarflexors to COM support. From this
muscle-actuated forward dynamic simulation of healthy slow gait, we concluded that
healthy individuals maintain COM support at slow speeds via minor modifications
to the muscle coordination pattern associated with normal speed walking
(i.e., increased contributions of knee extensors and enhanced stiffness due to
ankle dorsiflexors).
Higginson et al. (2006)
subsequently developed the first muscle-actuated forward dynamic simulation
based on the kinematic and kinetic data from a
complete cycle of post-stroke hemiparetic gait. The simulation framework used previously was enhanced to permit
asymmetric kinematics and muscle control. During gait for an individual
with post-stroke hemiparesis, adequate COM support is
provided via reorganized muscle coordination patterns of the paretic
and non-paretic lower limbs relative to healthy slow gait (i.e.,
co-activation of paretic muscles). Higginson et
al. (2006) have also used perturbation studies to investigate the effect
of equinus foot placement, a common movement
abnormality, on musculoskeletal dynamics. In a forward dynamic
simulation of normal walking, we augmented ankle plantarflexion by 10° at initial contact and found that equinus posture alone (without concomitant changes in muscle forces) caused
the knee to hyperextend, while intrinsic force-length-velocity properties
of muscle diminished the effect of equinus posture alone. Our preliminary work is exemplary of our proficiency
with experimental and computational techniques related to the study of
muscle coordination in individuals with post-stroke hemiparesis.
Research Plan
Omitted
Software Contributions
- Simulated
parallel annealing by neighborhood (
SPAN
)
will be posted on SimTK.org. This parallel implementation of the
global search algorithm expedites time to convergence for large-scale
simulations of human movement by at least a factor of 20 (Higginson et al., 2005).
- New
simulations of post-stroke hemiparetic gait,
which represent a range of gait abnormalities, will be posted
with initial conditions, muscle excitation patterns and movies on
SimTK.org.