The process of designing integrated biological systems across scales is difficult, with challenges arising from the modeling, understanding, and search of complex system design spaces. This paper explores these challenges through consideration of how stochastic nanoscale phenomenon relate to higher level systems functioning across many scales. A domain-independent methodology is introduced which uses multi-agent simulations to predict emergent system behavior and structure–behavior–function (SBF) representations to facilitate design space navigation. The methodology is validated through a nanoscale design application of synthetic myosin motor systems. In the multi-agent simulation, myosins are independent computational agents with varied structural inputs that enable differently tuned mechanochemical behaviors. Four synthetic myosins were designed and replicated as agent populations, and their simulated behavior was consistent with empirical studies of individual myosins and the macroscopic performance of myosin-powered muscle contractions. However, in order to configure high performance technologies, designers must effectively reason about simulation inputs and outputs; we find that counter-intuitive relations arise when linking system performance to individual myosin structures. For instance, one myosin population had a lower system force even though more myosins contributed to system-level force. This relationship is elucidated with SBF by considering the distribution of structural states and behaviors in agent populations. For the lower system force population, it is found that although more myosins are producing force, a greater percentage of the population produces negative force. The success of employing SBF for understanding system interactions demonstrates how the methodology may aid designers in complex systems embodiment. The methodology's domain-independence promotes its extendibility to similar complex systems, and in the myosin test case the approach enabled the reduction of a complex physical phenomenon to a design space consisting of only a few critical parameters. The methodology is particularly suited for complex systems with many parts operating stochastically across scales, and should prove invaluable for engineers facing the challenges of biological nanoscale design, where designs with unique properties require novel approaches or useful configurations in nature await discovery.

References

References
1.
Howard
,
J.
,
2001
,
Mechanics of Motor Proteins and the Cytoskeleton
,
Sinauer Associates, Inc.
,
Sunderland, MA
.
2.
Guckenheimer
,
J.
, and
Ottino
,
J. M.
,
2008
, “
Foundations for Complex Systems Research in the Physical Sciences and Engineering, Report From an NSF Workshop
.” Available at http://math.arizona.edu/~lega/nsf_complex_systems.pdf
3.
Cohen
,
I.
, and
Harel
,
D.
,
2007
, “
Explaining a Complex Living System: Dynamics, Multi-Scaling and Emergence
,”
J. R. Soc. Interface
,
4
, pp.
175
182
.10.1098/rsif.2006.0173
4.
Vattam
,
S.
,
B.
Wiltgen
,
M.
Helms
,
A.
Goel
, and
J.
Yen
,
2010
, “
Dane: Fostering Creativity in and Through Biologically Inspired Design
,”
International Conference on Design Creativity
,
Kobe, Japan
.
5.
Van Den Heuval
,
M. G. L.
, and
Dekker
,
C.
,
2007
, “
Motor Proteins at Work for Nanotechnology
,”
Science
,
317
, pp.
333
336
.10.1126/science.1139570
6.
Lv
,
S.
,
Dudek
,
D. M.
,
Cao
,
Y.
,
Balamurali
,
M. M.
,
Gosline
,
J.
, and
Li
,
H.
,
2010
, “
Designed Biomaterials to Mimic the Mechanical Properties of Muscles
,”
Nature
,
465
, pp.
69
73
.nature02303/nature09024
7.
Bakewell
,
D. J. G.
, and
Nicolau
,
D. V.
,
2007
, “
Protein Linear Molecular Motor-Powered Nanodevices
,”
Aust. J. Chem.
,
60
, pp.
314
332
.10.1071/CH06456
8.
Korten
,
T.
,
Mansson
,
A.
, and
Diez
,
S.
,
2010
, “
Towards the Application of Cytoskeletal Motor Proteins in Molecular Detection and Diagnostic Devices
,”
Curr. Opin. Biotechnol.
,
21
, pp.
477
488
.10.1016/j.copbio.2010.05.001
9.
Chi
,
M.
,
2005
, “
Commonsense Conceptions of Emergent Processes: Why Some Misconceptions Are Robust
,”
J. Learn. Sci.
,
14
(
2
), pp.
161
199
.10.1207/s15327809jls1402_1
10.
Deguet
,
J.
,
Demazeau
,
Y.
, and
Magnin
,
L.
,
2006
, “
Elements About the Emergence Issue: A Survey of Emergence Definitions
,”
Complexus
,
3
, pp.
24
31
.10.1159/000094185
11.
Bar-Yam
,
Y.
,
2004
, “
A Mathematical Theory of Strong Emergence Using Multiscale Variety
,”
Complexity
,
9
(
6
), pp.
15
24
.10.1002/cplx.20029
12.
Dessalles
,
J. L.
,
Ferber
,
J.
, and
Phan
,
D.
,
2008
, “
Emergence in Agent Based Computational Social Science: Conceptual, Formal and Diagrammatic Analysis
,”
Intell. Complex Adapt. Systems
,
24
, pp.
1
24
.
13.
Gilbert
,
N.
, and
Troitzsech
,
K.
,
2005
,
Simulation for the Social Scientist
,
Open University Press
,
New York, NY
.
14.
Vattam
,
S. S.
,
Goel
,
A. K.
,
Rugaber
,
S.
,
Hmelo-Silver
,
C. E.
,
Jordan
,
R.
,
Gray
,
S.
, and
Sinha
,
S.
,
2011
, “
Understanding Complex Natural Systems by Articulating Structure-Behavior-Function Models
,”
Educ. Technol. Soc.
,
14
(
1
), pp.
66
81
.
15.
Hmelo-Silver
,
C. E.
,
Marathe
,
S.
, and
Liu
,
L.
,
2007
, “
Fish Swim, Rocks Sit, and Lungs Breathe: Expert-Novice Understanding of Complex Systems
,”
J. Learn. Sci.
,
16
, pp.
307
331
.10.1080/10508400701413401
16.
Neiman
,
V. J.
, and
Varghese
,
S.
,
2011
, “
Synthetic Bio-Actuators and Their Applications in Biomedicine
,”
Smart Struct. Syst.
,
7
(
3
), pp.
185
198
.
17.
Bach
,
A. D.
,
Beier
,
J. P.
,
Stern-Staeter
,
J.
, and
Horch
,
R. E.
,
2004
, “
Skeletal Muscle Tissue Engineering
,”
J. Cell. Mol. Med.
,
8
(
4
), pp.
413
422
.10.1111/j.1582-4934.2004.tb00466.x
18.
Oldfors
,
A.
, and
Lamont
,
P. J.
,
2008
, “
Thick Filament Diseases
,”
Adv. Exp. Med. Biol.
,
642
, pp.
78
81
.10.1007/978-0-387-84847-1
19.
Armel
,
T. Z.
, and
Leinwand
,
L. A.
,
2010
, “
A Mutation in the Beta-Myosin Rod Associated With Hypertrophic Cardiomyopathy has an Unexpected Molecular Phenotype
,”
Biochem. Biophys. Res. Commun.
,
391
(
1
), pp.
352
356
.10.1016/j.bbrc.2009.11.062
20.
Ito
,
K.
,
Ikebe
,
M.
,
Kashiyama
,
T.
,
Mogami
,
T.
,
Kon
,
T.
, and
Yamamoto
,
K.
,
2007
, “
Kinetic Mechanism of the Fastest Motor Protein, Chara Myosin
,”
J. Biol. Chem.
,
282
(
27
), pp.
19534
19545
.10.1074/jbc.M611802200
21.
Patino-Lopez
,
Aravind
,
G.
,
L.
,
Dong
,
X.
,
Kruhlak
,
M. J.
,
Ostap
,
E. M.
, and
Shaw
,
S.
,
2010
, “
Myosin 1g is an Abundant Class I Myosin in Lymphocytes Whose Localization at the Plasma Membrane Depends on Its Ancient Divergent Pleckstrin Homology (Ph) Domain (Myo1ph)
,”
J. Biol. Chem.
,
285
(
12
), pp.
8675
8686
.10.1074/jbc.M109.086959
22.
Koenderink
,
G. H.
,
Dogic
,
Z.
,
Nakamura
,
F.
,
Bendix
,
P. M.
,
Mackintosh
,
F. C.
,
Hartwig
,
J. H.
,
Stossel
,
T. P.
, and
Weitz
,
D. A.
,
2009
, “
An Active Biopolymer Network Controlled by Molecular Motors
,”
Proc. Natl. Acad. Soc. U.S.A.
,
106
(
36
), pp.
15192
15197
.10.1073/pnas.0903974106
23.
Leduc
,
P. R.
, and
Robinson
,
D. N.
,
2007
, “
Using Lessons From Cellular and Molecular Structures for Future Materials
,”
Adv. Mater.
,
19
, pp.
3761
3770
.10.1002/adma.200701286
24.
Leduc
,
P. R.
, and
Bellin
,
R. M.
,
2006
, “
Nanoscale Intracellular Organization and Functional Architecture Mediating Cellular Behavior
,”
Ann. Biomed. Eng.
,
34
(
1
), pp.
102
113
.10.1007/s10439-005-9008-1
25.
Tsiavaliaris
,
G.
,
Fujita-Becker
,
S.
, and
Manstein
,
D. J.
,
2004
, “
Molecular Engineering of a Backwards-Moving Myosin Motor
,”
Nature
,
427
, pp.
558
561
.10.1038/nature02303
26.
Hodges
,
A. R.
,
Krementsova
,
E. B.
, and
Trybus
,
K. M.
,
2007
, “
Engineering the Processive Run Length of Myosin V
,”
J. Biol. Chem.
,
282
(
37
), pp.
27192
27197
.10.1074/jbc.M703968200
27.
Randall
,
D.
,
Burggren
,
W.
, and
French
,
K.
,
2001
,
Eckert Animal Physiology: Mechanisims and Adaptations
,
W.H. Freeman and Company
,
New York
.
28.
Resnicow
,
D. I.
,
Deacon
,
J. C.
,
Warrick
,
H. M.
,
Spudich
,
J. A.
, and
Leinwand
,
L. A.
,
2010
, “
Functional Diversity Among a Family of Human Skeletal Muscle Myosin Motors
,”
Proc. Natl. Acad. Soc. U.S.A.
,
107
(
3
), pp.
1053
1058
.10.1073/pnas.0913527107
29.
Weiss
,
S.
,
Rossi
,
R.
,
Pellegrino
,
M.
,
Bottinelli
,
R.
, and
Geeves
,
M. A.
,
2001
, “
Differing Adp Release Rates From Mosin Heavy Chain Isoforms Define the Shortening Velocity of Skeletal Muscle Fibers
,”
J. Biol. Chem.
,
276
(
49
), pp.
45902
45908
.10.1074/jbc.M107434200
30.
Images of Two-Stroke Motor and RC Aircraft are Copyrighted by http://www.RC-Airplane-Advisor.com/ and http://www.RC-Airplanes-Simplified.com/, Images Were Retrieved Mar. 21, 2012 and Modified for This Study.
31.
Campbell
,
M. I.
,
Cagan
,
J.
, and
Kotovsky
,
K.
,
1999
, “
A-Design: An Agent-Based Approach to Conceptual Design in a Dynamic Environment
,”
Res. Eng. Des.
,
11
, pp.
172
192
.10.1007/s001630050013
32.
Ottino
,
J. M.
,
2004
, “
Engineering Complex Systems
,”
Nature
,
427
, p.
399
.10.1038/427399a
33.
Pretz
,
J.
,
2008
, “
Intuition Versus Analysis: Strategy and Experience in Complex Everyday Problem Solving
,”
Mem. Cognit.
,
36
(
3
), pp.
554
566
.10.3758/MC.36.3.554
34.
Gero
,
J. S.
, and
Kannengiesser
,
U.
,
2003
, “
The Situated Function-Behaviour-Structure Framework
,”
Des. Stud.
,
25
(
4
), pp.
373
391
.10.1016/j.destud.2003.10.010
35.
Sneddon
,
M.
,
Faeder
,
J. R.
, and
Emonet
,
T.
,
2011
, “
Efficient Modeling, Simulation and Coarse-Graining of Biological Complexity With NFSim
,”
Nature Methods
,
8
(
2
), pp.
177
185
.10.1038/nmeth.1546
36.
Olsen
,
J.
,
Cagan
,
J.
, and
Kotovsky
,
K.
,
2009
, “
Unlocking Organizational Potential: A Computational Platform for Investigating Structural Interdependence in Design
,”
ASME J. Mech. Des.
,
131
(3), p. 031001.10.1115/1.3066501
37.
Landry
,
L.
, and
Cagan
,
J.
,
2011
, “
Protocol-Based Multi-Agent Systems: Examining the Effect of Diversity, Dynamism, and Cooperation in Heuristic Optimization Approaches
,”
ASME J. Mech. Des.
,
133
, p.
021001
.10.1115/1.4003290
38.
Schwaiger
,
I.
,
Sattler
,
C.
,
Hostetter
,
D. R.
, and
Rief
,
M.
,
2002
, “
The Myosin Coiled-Coil is a Truly Elastic Protein Structure
,”
Nature Mater.
,
1
(
4
), pp.
232
235
.10.1038/nmat776
39.
Nath
,
D.
,
2010
, “
Cell Biology: Myosin in Motion
,”
Nature
,
468
, p.
43
.10.1038/468043a
40.
Spudich
,
J.
, and
Sivaramakrishnan
,
S.
,
2010
, “
Myosin Vi: An Innovative Motor That Challenged the Swinging Lever Arm Hypothesis
,”
Nat. Rev. Mol. Cell Biol.
,
11
(
2
), pp.
128
137
.10.1038/nrm2833
41.
Anson
,
M.
,
Geeves
,
M. A.
,
Kurzawa
,
S. E.
, and
Manstein
,
D. J.
,
1996
, “
Myosin Motors With Artificial Lever Arms
,”
EMBO J.
15
(
22
), pp.
6069
6074
.
42.
Murphy
,
C. T.
, and
Spudich
,
J. A.
,
1998
, “
Dictyostelium Myosin 25–50k Loop Substitutions Specifically Affect Adp Release Rates
,”
Biochemistry
,
37
, pp.
6738
6744
.10.1021/bi972903j
43.
Sweeney
,
H. L.
,
Rosenfeld
,
S. S.
,
Brown
,
F.
,
Faust
,
L.
,
Smith
,
J.
,
Xing
,
J.
,
Stein
,
L. A.
, and
Sellers
,
J. R.
,
1998
, “
Kinetic Tuning of Myosin Via a Flexible Loop Adjacent to the Nucleotide Binding Pocket
,”
J. Biol. Chem.
,
273
(
11
), pp.
6262
6270
.10.1074/jbc.273.11.6262
44.
Piazzesi
,
G.
, and
Lombardi
,
V.
,
1995
, “
A Cross-Bridge Model That is Able to Explain Mechanical and Energetic Properties of Shortening Muscle
,”
Biophys. J.
,
68
, pp.
1966
1979
.10.1016/S0006-3495(95)80374-7
45.
Chin
,
L.
,
Yue
,
P.
,
Feng
,
J. J.
, and
Seow
,
C. Y.
,
2006
, “
Mathematical Simulation of Muscle Cross-Bridge Cycle and Force-Velocity Relationship
,”
Biophys. J.
,
91
, pp.
3653
3663
.10.1529/biophysj.106.092510
46.
Cuda
,
G.
,
Pate
,
E.
,
Cooke
,
R.
, and
Sellers
,
J. R.
,
1997
, “
In Vitro Actin Filament Sliding Velocities Produced by Mixtures of Different Types of Myosin
,”
Biophys. J.
,
72
, pp.
1767
1779
.10.1016/S0006-3495(97)78823-4
47.
Egan
,
P.
,
Leduc
,
P.
,
Cagan
,
J.
, and
Schunn
,
C.
,
2011
, “
A Design Exploration of Genetically Engineered Myosin Motors
,”
Design Automation Conference
,
Washington DC
.
48.
Tanner
,
B. C. W.
,
Daniel
,
T. L.
, and
Regnier
,
M.
,
2007
, “
Sarcomere Lattice Geometry Influences Cooperative Myosin Binding in Muscle
,”
PLOS Comput. Biol.
,
3
(
7
), pp.
1195
1211
.10.1371/journal.pcbi.0030115
49.
Campbell
,
K.
,
2009
, “
Interactions Between Connected Half-Sarcomeres Produce Emergent Mechanical Behavior in a Mathematical Model of Muscle
,”
PLOS Comput. Biol.
,
5
(
11
), p. e1000560.10.1371/journal.pcbi.1000560
50.
Cooke
,
R.
,
White
,
H.
, and
Pate
,
E.
,
1994
, “
A Model of the Release of Myosin Heads From Actin in Rapidly Contracting Muscle Fibers
,”
Biophys. J.
,
66
, pp.
778
788
.10.1016/S0006-3495(94)80854-9
51.
Harada
,
Y.
,
Sakurada
,
K.
,
Aoki
,
T.
,
Thomas
,
D. D.
, and
Yanagida
,
T.
,
1990
, “
Mechanochemical Coupling in Actomyosin Energy Transduction Studied by in Vitro Movement Assay
,”
J. Mol. Biol.
,
216
, pp.
49
68
.10.1016/S0022-2836(05)80060-9
52.
Ryschon
,
T. W.
,
Fowler
,
M. D.
,
Wysong
,
R. E.
,
Anthony
,
A. R.
, and
Balaban
,
R. S.
,
1997
, “
Efficiency of Human Skeletal Muscle in Vivo: Comparison of Isometric, Concentric, and Eccentric Muscle Action
,”
J. Appl. Physiol.
,
83
, pp.
867
894
.
53.
Manstein
,
D. J.
,
2004
, “
Molecular Engineering of Myosin
,”
R. Soc.
,
359
, pp.
1907
1912
.
54.
Piazzesi
,
G.
,
Reconditi
,
M.
,
Linari
,
M.
,
Lucii.
,
L.
,
Bianco.
,
P.
,
Brunello.
,
E.
,
Decostre.
,
V.
,
Stewart.
,
A.
,
Gore
,
D. B.
,
Irving
,
T. C.
,
Irving
,
M.
, and
Lombardi
,
V.
,
2007
, “
Skeletal Muscle Performance Determined by Modulation of Number of Myosin Motors Rather Than Motor Force or Stroke Size
,”
Cell
,
131
, pp.
784
795
.10.1016/j.cell.2007.09.045
55.
Uyeda
,
T.
,
Abramson
,
P.
, and
Spudich
,
J.
,
1996
, “
The Neck Region of the Myosin Motor Domain Acts as a Lever Arm to Generate Movement
,”
Proc. Natl. Acad. Sci. U.S.A.
,
93
, pp.
4459
4464
.10.1073/pnas.93.9.4459
56.
Egan
,
P.
,
Leduc
,
P.
,
Cagan
,
J.
, and
Schunn
,
C.
,
2012
, “
Design of Complex Nano-Scale Systems Using Multi-Agent Simulations and Structure-Behavior-Function Representations
,”
International Conference on Design Theory and Methodology
,
Chicago IL
.
57.
Agarwal
,
A.
, and
Hess
,
H.
,
2010
, “
Biomolecular Motors at the Intersection of Nanotechnology and Polymer Science
,”
Prog. Polym. Sci.
,
25
, pp.
252
277
.10.1016/j.progpolymsci.2009.10.007
You do not currently have access to this content.