Urry D.W. (Ed.) What Sustains Life? : Consilient Mechanisms for Protein-Based Machines and Materials

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E.4 Protein-based Machines as Physical Embodiments of the "Vital Force" That Sustains Life

555

y-rotor rather than behind it in position

to push the rotor in the expected counter-

clockwise direction (see immediately

below).

Prediction 8: AGap drives counterclockwise

rotation of the FrATPase rotor. As was

shown in Figure

8.41,

the AGap-derived repul-

sive force between S04^~ and the y-rotor that

causes movement "in opposite directions" of

the PE-ADP-S04^" and y-subunits in Figures

E.2 through E.4 would provide a counter-

clockwise rotational impulse to the y-rotor, as

demonstrated by Noji et

al.^^

The same con-

clusion was reached by Menz et al.,^^ as indi-

cated by the statement that "the observed

rotation of the y subunit is consistent with the

sense of rotation seen in the direct visualiza-

tion experiments (Noji et al., 1997) "

The success of the above set of predictions

concerning structure and function of the Fj-

ATPase (the Fi-motor of ATP synthase) demon-

strate a dominant role of the hydrophobic and

elastic consilient mechanisms in the function of

this pivotal protein-based machine of biology.

E.4J.3 Use of ATP to Perform

Mechanical Work of the Organism,

Chemo-mechanical Transduction by

the Myosin II Motor

E.4.1.3.1 Perspective of the Hydrophobic

Consilient Mechanism in the Performance

of Mechanical Work

Chemo-mechanical transduction technically

defines the use of chemical energy of ATP to

produce motion, as in muscle contraction. The

fundamental statement of the hydrophobic

consilient mechanism regarding chemo-

mechanical transduction is that the most

charged, polar states disrupt hydrophobic asso-

FiGURE E.3. Cross-eye stereo view in trace repre-

sentation from the top of the Fi-motor of ATP syn-

thase of the superposition of

two

structures, one with

the empty pE-site given in light gray and the second

with the ADP-S04-occupied Pn-subunit in dark gray.

An increase in mean distance between the y-rotor

and the PE-subunit is shown when the empty PE-

subunit is replaced by ADP-SO4 and when the SO4

fills the role of a stable analogue for hydrolyzed y-

phosphate. The doubly charged S04^" acts to free

charged side chains of the PE-subunit from ion

pairing and hydrogen bonding such that they will

also contribute to the total apolar-polar repulsion,

AGap, between the ADP-S04-occupied PE-subunit

and rotor. The resulting

AGap

applies a torque to the

double-stranded a-helical coiled coil section of the

y-rotor (residues 3-35 and 221-250 shown) that

would impart a counterclockwise rotation to the

rotor when functioning as the Fi-ATPase.^^ This is

shown more explicitly in Figure E.4 and especially in

Figures 8.40 and 8.41. (From Menz et al.^^ adapted

for cross-eye view with permission of Elsevier.)

556 Epilogue

Depicting Apolar-polar Repulsion in Structure 1H8E

a-ADP

chain C

FIGURE E.4. Cross-eye stereo view of the Fi-motor

of ATP synthase with y-rotor in ribbon and E and C

chains in space-filhng representation with residues

indicated as neutral in light gray, aromatic in black,

other hydrophobics in gray, and charged in white.

Lines indicate a repulsive interaction (i.e., AGap)

between the hydrophobic y-rotor and SO4 (in place

of hydrolyzed y-phosphate) and augmented by newly

emerged charged groups that occurs in the

chain.

The AGap due to SO4 and emerged charged groups

apply a torque to the double-stranded a-helical

coiled coil section of the y-rotor that would give a

counterclockwise rotation when functioning as an

ATPase. (Adapted from Urry "Function of the Fi-

motor (Fi-ATPase) of ATP synthase by Apolar-polar

Repulsion through Internal Interfacial Water." Cell

Biol Int., 30(1), 44-55, 2006. Prepared using

(Adapted from Urry.^^)

ciation and that the powerstroke due to the step

down from the most charged state drives

hydrophobic association. In regard to the uni-

versal energy coin of biology,

ATP"^"

Mg^^ rep-

resents the penultimate polar state; the ultimate

polar state of biology is ADP^" Mg^^ HPO/",

and the loss of HP04^- to leave ADP^" Mg^^

provides the largest single step impulse for

driving hydrophobic association. In short, from

the perspective of the hydrophobic consilient

mechanism, the powerstroke results from

hydrophobic association!

E.4 Protein-based Machines as Physical Embodiments of the "Vital Force" That Sustains Life

557

E.4.1.3.2 Structure of the Myosin II Motor

and the Sliding Filament Model of

Muscle Contraction

The myosin II motor produces the very famil-

iar motion resulting from contraction of skele-

tal muscle. From the gross anatomical

perspective, the motion of contraction derives

from the decrease in length between two sites

of muscle attachment. At the level of the elec-

tron microscopic, shortening results from short-

ening the length of the fundamental repeating

unit of muscle, the sarcomere. As shown in

Figure 8.45, shortening of the sarcomere length

defined by the distance between Z disks would

occur by the sliding into greater overlap of two

classes of filaments (myosin and actin) that

intersperse in hexagonal arrays such that 24

thin actin filaments separate and surround

seven thick myosin filaments. Long myosin mol-

ecules, staggered in their association to make

the thick filament, terminate in cross-bridges

that attach to the thin actin filaments. Each

cross-bridge contains a single nucleotide

binding site that functions as an ATPase, and

the breakdown of ATP to ADP with release of

Pi produces the motion of muscle contraction.

Thus,

contraction by the sliding filament model

of the foregoing construction requires cyclic

attachment/detachment from the actin filament

correlated with cyclic contraction/relaxation.

In our approach we look to the most polar

states associated with the use of ATP for dis-

ruption of hydrophobic association and to the

absence of such polar states as giving rise to

hydrophobic association. For the myosin II

motor, two crystal structures of the cross-bridge

from scallop muscle, due to Szent-Gyorgyi and

Cohen and their coUeagues,^^ provide the

opportunity for such an analysis. One structure

is called a near-rigor state without nucleotide,

but it does contain a polar sulfate, but partially

neutralized as the

Mg^"^

SO/~. At the active site

the other structure contains an analogue of

ATP^-

Mg'% namely, ADP^" Mg^^-BeFx (where

BeFx is to fill the role of the y-phosphate).

These two crystal structures do not provide

snapshots of the extremes that would be pre-

ferred, but they do allow useful comparisons of

two structures near the desired limits.

Starting from the prejudice of the hydropho-

bic and elastic consilient mechanisms and uti-

lizing the two noted structures, we proceed

within the framework of the sliding-filament

cross-bridge structure with a single nucleotide

binding site in each cross-bridge. In Chapter 8,

section 8.5.4, this conceptual context brought

to light a set of findings much as would be

expected from the understanding of the

hydrophobic and elastic consilient mechanisms

developed in Chapter 5. The following sum-

marizes these findings for the myosin II motor

in terms of a set of six expectations that we suc-

cinctly examine for extent of realization.

Expectation 1: That ATP binding at the cross-

bridge active site provides a AGap-based repul-

sive force for detachment by hydrophobic

dissociation from the actin filament. On occu-

pancy of an empty active site by the penul-

timate polar state, ATP"^" Mg^"^, disruption

of hydrophobic association becomes the

primary expectation of the hydrophobic con-

silient mechanism. Of course, ATP binding

disrupts cross-bridge binding to the actin fil-

ament, that is, disrupts the hydrophobic

association that provides for attachment of

cross-bridge to the actin filament. The

hydrophobic consilient mechanism requires,

however, that "waters of Thales" occur

between the phosphates of ATP and the site

of hydrophobic association in order that an

apolar-polar repulsive free energy of hydra-

tion, AGap, may exist between the two sites.

Expectation 5 and Figures E.5 and E.6

address with the structural feature whereby

the myosin II motor directs this AGap-based

repulsive force'.

Expectation 2: That the ADP plus Pi state at the

cross-bridge active site effects a repulsive

AGap force for dissociation of hydrophobic

domains within the cross-bridge. Relevance

of the hydrophobic consihent mechanism to

the motion of contraction requires that

formation of the most polar state, ADP^"

Mg^^ HPO/~, effects hydrophobic dissocia-

tion within the cross-bridge. This sets the

stage for the loss of Pi, that is, of HPO/", that

drives the hydrophobic association required

by the hydrophobic consilient mechanism as

558

Epilogue

N-terminal domain

with lever arm tucked

under it by means of

rophobic association

Tip of triangular scale

which overhangs cleft

to site of hydrophobic

association for

the powerstroke

Hydrophobic

hea<

of lever arm used

in powerstroke

FIGURE E.5. Stereo view (cross-eye) in space-filling

representation of the scallop muscle cross-

bridge(Sl) viewed approximately from the side of

the actin binding site on myosin cross-bridge for the

purpose of locating the narrow clefts that direct the

apolar-polar repulsive force. (A) The hydrophobic

association of the near-rigor state. (Prepared using

the crystallographic results of Himmel et al.^ as

obtained from the Protein Data Bank, Structure File

1KK7.)

(B)

The hydrophobic dissociation of the ATP

analogue state. (Prepared using the crystallographic

results of Himmel et al.^ as obtained from the

Protein Data Bank, Structure File 1KK8.)

the basis for the powerstroke. The very

apparent hydrophobic dissociation is seen in

Figure 8.51B, 8.52B, 8.53, and 8.54.

Expectation 3: That the rigor-like state demon-

strates a re-established hydrophobic associa-

tion that defined the powerstroke. Tht absence

of highly polar occupancy of the active site,

as in the near-rigor state show^n in Figure

E.5A, illustrates formation of hydrophobic

association between the head of the lever

arm and the underside of the amino-terminal

domain. This involves the very hydrophobic

residues L711, L712, L767, and F716 as well

as F707, F761, and F761, associated with

the head of the lever arm, and the very

hydrophobic residues of L94, Y93,1700, F28,

E.4 Protein-based Machines as Physical Embodiments of the "Vital Force" That Sustains Life

559

and F82 as well as proximal F119,

L118,

L697,

and V696, associated with the underside of

the amino-terminal domain. These hydro-

phobic residues accept exposure to water in

the structures in Figures E.5B and E.6 due to

the apolar-polar repulsive free energy of

hydration that emanates from the active site

as the result of occupancy by a sufficiently

polar state.

Expectation 4: That the hydrophobic associa-

tion of the powerstroke extends kinetically

free chain segments to produce an elastic

force. In order that there be a smooth and

efficient conversion of energy from chemical

to mechanical by the act of hydrophobic

association, the energy must be temporarily

stored in an elastic deformation with limited

hysteresis. This occurs as hydrophobic asso-

^.L..^

/Location of

Y*P)U)SliiU^

in active site at turn of

narrov^

cleft

'^ *

Narro

cleft

Narrow cleft to

hydrophobic associ

for the powerstroke

Narro^

cleft

' M'^

N-terminal domain

separated from the

lever arm due to

hydrophobic

dissociation

"" Y"Phosphate

sitelf^'-

" •

/' cN-terminal domain

^1i^ /separated from head

"\^^^^' of

the

lever arm

FIGURE E.6. Stereo view (cross-eye) of scallop

muscle cross-bridge(Sl) to show the ATP binding

site at the turn in a cleft. The cleft runs in two direc-

tions,

one toward the actin-cross-bridge binding site

and the other toward the hydrophobic dissociation

between the head of the lever arm and the amino-

terminal domain. (A) Space-filling representation.

(B) Ribbon representation. (Prepared using the crys-

tallographic results of Himmel et al.^^ as obtained

from the Protein Data Bank, Structure File 1KK8.)

560

Epilogue

ciation stretches interconnecting chain seg-

ments. A significant search has yet to occur

throughout the cross-bridge. Noted, however,

in Figure 8.52 and featured in Figure 8.55 is

the extension of an interconnecting chain

segment that occurs on going from the

hydrophobically dissociated state with ATP

analogue occupancy of the active site to

the hydrophobic association of the near rigor

state.

Here resides the coupling of the

hydrophobic and elastic consilient mecha-

nisms for the function of protein-based

machines.

As noted by Rayment and coworkers,^^ a

number of flexible loops occur in the cross-

bridge, and we suggest that these are poten-

tial sources for elastic force development

that results from hydrophobic association

of the powerstroke (see Chapter 8, section

8.5.4.5).

Expectation 5: That narrow clefts direct the

repulsive AGap force in two directions to

disrupt hydrophobic association of cross-

bridge-actin binding and to disrupt the

hydrophobic association responsible for the

powerstroke. As shown on Figure E.6, a

narrow cleft runs from the site of the cross-

bridge-actin binding to the active site where

it makes a sharp turn and runs directly to the

site for hydrophobic association between the

head of the lever arm and the hydrophobic

underside of the amino-terminal domain. In

terms of the hydrophobic consiUent mecha-

nism these clefts direct the thirst for hydra-

tion of the polar species in the active site

toward the sites of hydrophobic association.

The narrow clefts function as conduits to

direct the repulsive force due to the apolar-

polar repulsive free energy of hydration,

AGap, to interaction with sites for hydropho-

bic association. In Figure E.5, the cleft, con-

necting the y-phosphate of ATP to the

hydrophobic association between the head of

the lever arm and the underside of the

amino-terminal domain, runs under an over-

hang of a triangular surface scale identified

by residues P571-R560-F539 at the three

apices of the triangle. Figure E.6A allows a

look directly into this section of the cleft.

Expectation 6: That calcium ion triggers con-

traction by opening a hydrophobic site on

actin that hydrophobically associates with the

cross-bridge and increases the repulsive AGap

force on ADP plus Pi to expel P, that relieves

repulsion to drive the hydrophobic associa-

tion of the powerstroke. Introduction of the

process whereby calcium ion triggers con-

traction by the hydrophobic consilient

mechanism requires knowledge of the state

of ATP in the active site of the dissociated

cross-bridge and the state that binds to the

actin filament. In the ATP occupied state of

the detached cross-bridge, an active ATP <-^

ADP Pi interchange occurs that appears to

be more toward the hydrolyzed state.^^ Fur-

thermore, as noted by Lymn and Taylor^^

quite early, "actin binds with the myosin ADP

P complex and displaces products of the

hydrolysis reaction. It is concluded that this

step is responsible for activation of myosin

ATPase by actin." Thus the state of

nucleotide in the cross-bridge on binding to

the actin site would be the most polar state,

ADP^-

Mg^^ HPO/-. The description of the

process whereby calcium ion triggers con-

traction by binding to troponin C on the

actin filament is particularly well-suited to

description by the force resulting from the

apolar-polar repulsive free energy of hydra-

tion, AGap, of the hydrophobic consiUent

mechanism.

The essential result of calcium ion binding

is that it displaces tropomyosin to open a

strong hydrophobic binding site on actin for

cross-bridge attachment. Hie attachment to

actin would close off a major source of hydra-

tion for the most polar state, ADP^" Mg^^

HPO/",

that was provided by the narrow cleft

connecting the active site to the cross-bridge-

actin binding site. This could raise the free

energy of the most polar state to such an

extent that lowering the free energy would be

achieved by expulsion of HPO/". With this

loss of phosphate, the apolar-polar repulsion

maintaining the hydrophobic dissociation at

the other end of the narrow cleft is lost such

that the hydrophobic association of the

powerstroke results.

E.5 Extraordinary Biomaterials Opportunities Arise

561

The above expectations that describe the

structure and function of the myosin II motor

suggest a dominant role for the hydrophobic

and elastic consilient mechanisms in the function

of this representative motor for producing

motion in living organisms.

E.4.1.4 Concluding Comment for Physical

Embodiments of the ''Vital Force''

We have discussed the nexus of hydrophobic

and elastic consihent mechanisms in Complex

III at the intersection of electron flow and

proton translocation (electro-chemical trans-

duction) that was unimaginable, absent the

detailed analysis of structure. The hydrophobic

and elastic consilient mechanisms, however,

when applied to the general structure and

phenomenology of the Fi-motor of ATP

synthase (chemo-chemical transduction), gave

rise to a host of successful predictions, and,

when applied to the structure and phenome-

nology of the myosin II motor (chemo-

mechanical transduction), resulted in a

half-

dozen realized expectations. These findings do

much to substantiate the relevance of the

hydrophobic and elastic consilient mechanisms

to the protein-based machines of biology.

The above three discussed protein-based

machines—Complex III of the electron trans-

port chain, ATP synthase/Fj-ATPase, and the

myosin II motor of muscle contraction—repre-

sent the three major classes of energy conversion

that sustain Life. Therefore, the facility with

which the consilient mechanisms explain their

function indeed support the thesis that biology's

"vital force" arises from the coupled hydropho-

bic and elastic consilient mechanisms.

When taken together, the successes of the

hydrophobic and consilient mechanisms in

describing the functions of these three represen-

tative classes of biological energy conversion

constitute a significant statement in favor of the

roles of these mechanisms as "vital forces" that

impart function to the protein-based machines

of biology.

E.5 Extraordinary Biomaterials

Opportunities Arise from

Identified Vital Forces,

Biocompatibility, and

Biosynthesis

E.5.1 An Enabling Triumvirate:

Knowledge of Vital Forces, Capacity

for Biosynthesis, and Elastic

Protein-based Polymers with

Unique BiocompatibiUty

E.5.1.1 An Enabling Triumvirate

The above-detailed successes of the hydro-

phobic and elastic consilient mechanisms in

describing the functions of multifaceted pro-

teins of biology herald an historic naissance for

biomaterials innovation. Singularity arises from

the near-simultaneous emergence of three

developments: (1) the deepened understanding

of the forces that provide the basis for protein

function, (2) the unparalleled capacity to

produce diverse protein-based materials by

recombinant DNA technology, and (3) the

remarkable biocompatibility of elastic protein-

based polymers. Achieving an emerging

command of the vital forces that underpin

living organisms points to the design of protein-

based polymers with the capacity to perform

the desired tasks of biomaterials with the speci-

ficity, selectivity, and efficiency that attend

biology's own protein function.

E.5.1.2 Each Application Warrants a

Specifically Optimized Sequence

This brings us in an unprecedented way to the

circumstance envisioned by Jacob Bronowski

in his 1973 book. Ascent of Man,^^ where he

stated, "In effect, the modern problem is no

longer to design a structure from the materials

(available) but to design materials for a struc-

ture." We are now in the position to design

protein-based polymers for each specific appli-

562

Epilogue

cation. The past has seen coercion of function

by chemical treatments and physical manipula-

tion of a single starting polymer composition.

Now, whenever an application is defined,

response can be the design of a unique

protein-based polymer with a specified and

application-optimized sequence. Often the

basic consideration becomes the apolar-polar

repulsive free energy of hydration,

AGap,

within

the chain that results from the repulsive inter-

action of the charged and hydrophobic groups.

E.5.1.3 Mechanical Resonances Are Key

to Biocompatibility and Certain Medical

and Nonmedical Applications

For medical applications, in our view, mechan-

ical resonances (see Section 9.4.2.3)^^ present

barriers to antibody interaction such that these

soft elastic biomaterials exhibit a remarkable

biocompatibility otherwise considered impossi-

ble for "foreign proteins." As a specific example

for medical and nonmedical applications, the

author beUeves that the finding of mechanical

resonances, so innovative as to be denounced as

artifact by those constrained by the "idols of the

present,"^^ constitutes opportunities for the

future ranging from biosensors capable of

single molecule detection to hearing protection

and underwater sound absorption.

E.5.2 Medical Devices Using

Biology's Own Mechanisms

and Materials

E.5.2,1 The

Consilient

Approach to

Medical Devices

Here again the adjective consilient becomes

relevant. In the present context there occurs

"a common groundwork of explanation"^ for

function within the medical device, within the

patient for whom support is being designed,

and between device and patient. The consilient

approach, therefore, employs the same hydro-

phobic and elastic consilient mechanisms in the

design of the medical device that operate at the

site of appUcation, as demonstrated in Chapters

6, 7, 8, and 9 and above in section E.4.

E.5.2.2 The Consilient Approach to Soft

Tissue Engineering

E.5.2.2.1 The Concept of the Consilient

Approach to Soft Tissue Engineering

As stated in Chapter 9, "The consilient

approach to tissue engineering utilizes

biology's own materials and mechanisms, con-

cerned with tissue structure and function, to

achieve tissue restoration." The key materials

elements are three: the capacity of the elastic

protein-based material to match the elastic

modulus of the tissue to be restored, a remark-

able biocompatibility of the pure elastic

protein-based material, and the facility to

design into the protein-based polymer

sequence any desired biologically active

sequence, which, by virtue of the innocuousness

of the elastic protein-based material, allows

proper expression of the incorporated biologi-

cally active sequence. This provides the oppor-

tunity for the proper functional relationship of

protein-based material to the cells and the

extracellular matrix of the tissue to be restored.

E.5.2.2.2 The Concept of Temporary

Functional Scaffoldings

It is our thesis that materials and tissue (extra-

cellular matrix and cells) function by the

hydrophobic and elastic consiUent mechanisms.

Importantly, the material can be designed to

contain the appropriate cell attachment

sequences for the natural cells of the tissue to

be restored. The natural cells of the tissue to be

restored can migrate into the material, attach,

and sense the tensional force changes that

occur during functioning of the prosthesis. As

cells are themselves mechano-chemical trans-

ducers, the magnitude and periodicity of the

tensional force changes to which the cells are

subjected induce the cells to produce the extra-

cellular matrix sufficient to sustain those force

changes. The concept continues; in the normal

ongoing remodeling process the natural cells

within the prosthesis remodel it into a natural

tissue as the protein-based prosthesis is

replaced by an appropriate rate of degradation.

The concept of a temporary functional

scaf-

folding for soft tissue restoration is temporary

E.5 Extraordinary Biomaterials Opportunities Arise

563

in that it can be set for an appropriate rate of

degradation and

functional because it has the

appropriate elastic modulus with which to fill

the mechanical role of prosthesis, and it con-

tains cell attachment sequences whereby the

cells interact and sense the demand on the

tissue that they remodel into the natural tissue.

E.5.2.3 The Central Role of AGap in the

Controlled Release of Pharmaceuticals

E.5.2.3.1 AGap Sequence Energizes

Protein-based Polymers for Function

The competition for hydration between

charged and hydrophobic groups constrained

by sequence to coexist in a chain molecule

energizes the chain molecule as these disparate

groups reach out for hydration spheres unper-

turbed by the other. This gives rise to an

apolar-polar repulsive free energy of hydra-

tion,

AGap,

that energizes a particular sequence.

As the repulsion becomes greater, the charges

become driven toward charge neutralization

by ion pairing. The hydrophobic induced pKa

shift provides a measure of the extent of the

repulsion, that is, of AGap.

When the pH is not suitable, instead of neu-

tralization by protonation of a carboxylate, for

example, ion pairing becomes the possible

means of neutralization. Ion pairing, however,

only lowers the free energy about half as well

as protonation. Nonetheless, ion pairing pro-

vides a most useful force as in the process of

aligning complementary chains and in loading

charged drug into interaction with an op-

positely charged polymer. With regard to

the charged-drug-oppositely-charged-polymer

interaction, increased hydrophobicity of the

polymer enhances drug affinity and decreases

release rate of drug.

E.5.2.3.2 Drug Delivery by Trtype

(Transductional) Protein-based Polymers

Another aspect of ion pairing to lower AGap is

lowering the temperature of the inverse tem-

perature transition. This means that the oppo-

sitely charged polymer can be soluble, because

the onset temperature for the transition, Tt, is

above physiological temperature. The effect of

ion pairing with the pharmaceutical, as part of

lowering AGap, is to lower the value of Tt such

that ion pairing drives the phase separation.

Therefore, the phase-separated state

becomes the drug delivery vehicle, and one of

such a nature that on release of the drug the

vehicle itself disperses. This means for a con-

stant surface area that there occurs a zero order

release of drug, as shown in Figure E.7 for

positively charged Leu-enkephalin amide ion

pairing with carboxylate-containing protein-

based polymers. By polymer design the number

of ion pairing sites determines the density of

drug in the drug delivery vehicle, and the level

of drug release is inversely proportional to the

intensity and number of hydrophobic groups.

Thus,

as shown in Figure E.7, a remarkable

control of pharmaceutical release is possible.

Furthermore, the pharmaceutical can vary all

the way from a simple bare cation or anion

to a protein or nucleic acid. Under favorable

circumstances, as with carboxylate groups,

the vehicle disappears as the pharmaceutical

releases. With a cationic polymer such as a

lysine-containing protein-based polymer, the

chloride ion can displace the pharmaceutical to

lessen the zero order release. Significantly, with

elastic protein-based polymers, no fibrous

capsule forms around the adequately purified

polymer such that this does not affect the

release process.

This enabling triumvirate—knowledge of the

vital forces (e.g., AGap), the capacity for precise

control of desired sequence, and extraordinary

biocompatibility—provides controlled release of

pharmaceuticals to an extent that has only now

become possible.

E.5.2.4 The Central Role of AGap for

Production of Fibers with Superior

Physical Properties

The issue of communication between mole-

cules enters into the consideration of "order

out of chaos" as discussed below. The specific

aspect of communication between molecules

here involves the association of complementary

chains to achieve aligned and cross-linked poly-

mers.

One area where this has application is in

fiber formation. In this case, one chain mole-

564

Epilogue

Release of Leu-enkephalin amide from

Glu-containing Protein-based Polymers

7.5-

I "^

2.5-

250 mg polymer

Loading conditions: pH

6.8

1.5 equivalents of drug

per Glu(E) binding site

O PolyCGVGFP GEGFP

GVGVP):

pKa = 4.9; ApKa = 0.9

D Poly(GEGVP GVGVP GVGFP GFGFP GVGVP GVGVP)

pKa =

4.9;

ApKa =

0.9

• Poly(GFGFP GEGFP

GFGFP):

pKa = 6.2; ApKa = 2.2

4.7 mole

2.6 mole

1.85

mole

"T"

FIGURE E.7. Controlled release of positively charged

Leu-enkephalin amide (ff-Tyr-Gly-Gly-Phe-Leu-

NH2,

LEA^) from negatively charged polymers with

systematically increased hydrophobicity with ApKa

values

0.9,1.3,

and

2.2,

giving AG.p values

L27,

L84,

and

3.12kcal/mole-E, respectively. Constant

cules

designed with

repeating negative

charge,

for

example,

carboxylate,

and the

other with

the

same periodicity

of a

positively

charged amino group. When neither

these

sequences

has

hydrophobic induced

pKa

values,

the

affinity

water

minimal.

However, when

one or

both

of the

comple-

mentary molecules

has

hydrophobic induced

pKa shifts, that

is, a

significant AGap within

chain molecule, then there exists

driving force

for

ion

pairing

carboxylate with amino.

Ion-

paired groups, carboxylate

(-COO~)

with

amino (-NHs^),

are in

position

for

chemical

cross-linking

form

amide cross-link.

Knowledge

of the

vital force, AGap,

and the

capacity

for

precise control

sequence allows

for

the

formation

fibers with improved

elastic moduli, break strains,

and

stresses,

shown

Figure

9.20.

number

medical uses

for such fibers include sutures

and

woven

meshes

for

vascular prostheses

and

hernial

repair. Again,

the

enabling triumvirate—knowl-

edge

the vital forces

(e.g.,

AGap),

the

capacity

for precise control

desired sequence,

and

extraordinary biocompatibility—provide addi-

60 80

100

days

surface area maintains zero order release levels

for

each polymer and 1.85 p.mole/day out to

months

for

a AGap

3.12kcal/mole-E. Initial burst release

due

to 50% excess drug over polymer sites. (Replotting

of Figure

9.38.)

tional medical devices of great potential for

improving health care.

E.5.3 Nonmedical

(and

Medical)

Devices Using Biology's

Mechanisms

and

Materials

The enabling triumvirate provides the antithe-

sis to Pandora's box. Instead of being a prolific

source of troubles, the enabling triumvirate

provides a prolific source of opportunities with

which to overcome today's troubles. Even at

this early stage, with all that is already under-

way and that which is just emerging, it becomes

difficult to choose the applications to empha-

size here. The choice makes note of nano-

sensors and uses of mechanical resonances as

representative of exciting and emerging possi-

bilities. Mechanical resonances contribute to

applications from the relatively mundane of

sound absorption for civilian and naval appli-

cations to the exotic opportunity of nano-

sensors with potential use in the field to detect

terrorist chemical and biological agents. The

future can be one of nanosensors with the