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General Principles

Most measurements reflect average behavior of a

population of biopolymers.

– e.g., a protein’s native state is an average over many similar

conformations, all of which exhibit activity.

Statistical Thermodynamics allows a discussion of:

– how a population is distributed over the accessible states;

– the resulting mean values of the physical properties.

Two types of “average” behavior:

– time-average of a single molecule;

– instantaneous average over an ensemble of molecules.

Fundamental Assumption:

– time-average and ensemble-average behaviors are

identical.

Modeling Structural Transitions

Statistical Thermodynamics most useful for modeling

phenomena involving multiple states:

– transitions between biopolymer states;

– assembly of complexes from multiple subunits;

– binding of multiple ligands to macromolecules.

Our focus: Modeling Structural Transitions

– Formalism originally developed to predict biopolymer melting;

– also useful for predicting protein/nucleic acid structural

transitions.

Outline:

– Lecture 9: Intro. to Modeling Structural Transitions.

– Lecture 10: Structural Transitions in Polypeptides/Proteins.

– Lecture 11-12: Structural Transitions in Nucleic Acids.

Lecture 9 – Introduction to

Modeling Structural Transitions

Modeling The Two-State Transition

In the simplest case:

– A biopolymer is modeled as having two only states, A and

B.

– if the two forms are at equilibrium, ‘mass action’ gives:

– a large number of identically prepared systems;

• roughly 1023 copies.

– which is at equilibrium; (constant V, P, N, T)

What is the probability/member of occupying B?

– From simple probability considerations and the law of mass

action, we know:

P = [B]/([A]+[B]) = K /(1+K ).

The Statistical Weight

Let state A be defined as the ‘reference state’…

– energies of all conformations then defined relative to that of

the ref. state.

• generally, this is defined as our state of zero free energy.

Then, let the statistical weight (ωi) of any state i:

– also be defined relative to the reference state,

• in terms of relative equilibrium concentrations.

– For our simple, 2-state system, we have 2 weights:

ωA = [A]/[A] = 1 ωB = [B]/[A] = Keq

Generality of the Statistical Weight

ωi appears to be a simple redefinition of Keq.

– however, ωi is more general:

• Keq is a macroscopic measure of all products to all reactants.

– often includes several ‘pathways’…

• In contrast, ωi relates occupancies of each state, i.

– to that of the reference state, of weight ωo.

– ω is essentially a micro-equilibrium constant;

• very useful for systems with more than two states.

How do we estimate statistical weights,

– for a physical system of interest?

• by computing the ‘Gibbs Factors’.

The Gibbs Factor

At equilibrium, the statistical weight, ωj of state j:

– is related to the standard Gibbs free energy (Gjo) of

formation of state j…

• relative to the free energy (Goo) of the reference state:

– In particular, ωj = exp[-∆Gjo/RT];

• R = molar gas constant.

– In this form, ωj is called the Gibbs Factor.

For our 2-state system, PB can be rewritten:

– in terms of the Gibbs factor of state B:

• PB = exp[-∆GBo/RT]/(1 + exp[-∆GBo/RT]).

The Partition Function, Q

The partition function, Q of a system,

– is the sum of the statistical weights of all system states:

• Q = Σi ωi = Σi exp[-∆Gio/RT].

– For our 2- state system:

• Q = exp[-∆GAo/RT] + exp[-∆GBo/RT]

= 1 + exp[-∆GBo/RT] .

Q facilitates computation of system probabilities:

– the equilibrium probability of occupying state j:

• Pj = ωj/Q = exp[-∆Gjo/RT]/Q.

Q also allows computation of ensemble average

quantities:

– such an the mean free energy or entropy of a biopolymer.

Computing Ensemble Averages

The ensemble average of observable quantity, X,

– at equilibrium…

– is computed from Q by simply taking a weighted average:

<X> = Σi Xi exp[-∆Gio/RT]) / Q = Σi Xi Pi.

• Here, Xi is the X value characteristic of state i.

<X> = (XA exp[-∆GAo/RT] + XB exp[-∆GBo/RT]) / Q.

= (XA + XB exp[-∆GBo/RT])/Q

– It turns out that every intrinsic macroscopic quantity

• will correspond to an ensemble average.

Q thus ‘contains’ a complete specification of the

system:

– if we know Q, we should be able to predict system behavior.

Example – 2 Flipped Coins

To illustrate probabilistic nature of our treatment:

– consider the simple, analogous example of 2 flipped coins.

Each coin can land either heads (h) or tails (t).

• 4 outcomes…hh, ht, th, tt (system microstates).

– System (both coins) can assume 3 macrostates (j):

• State ‘HH’: j = 2 heads…unique (g2 = 1…only hh).

• State ‘HT’: j = 1 head…degenerate (g1 = 2…ht and th).

• State ‘TT’: j = 0 heads…unique (g0 = 1…only tt).

…so the ‘macrostate’, j is the total number of heads.

Assume both coins are fair:

– So, the coin states (h, t) have equal weights of 1:

• ωh and ωt = 1.

Weight of each system macrostate, j is given by:

ωj = gj ωhjωt2-j

2 Flipped Coins: Average Quantities

Our ‘Partition Function’:

– given by the sum of the weights, taken over system states:

Q=Σｊ j = (1)(1)2(1)0+(2)(1)1(1)1+(1)(1)0(1)2= 4.

Probabilities of State Occupancy:

– for the 3 ‘macroscopic’ states, HH, HT, and TT

• PHH = ω2/Q = ¼,

• PHT = ω1/Q = 2/4 = ½,

• PTT = ω0/Q = ¼. (note: PHH + PHT + PTT = 1!)

– i.e., the mean number after many independent trials.

• estimated by a weighted average:

<H> = Σj j ωj/Q.

= [(2)(1) + (1)(2) + (0)(1)] / 4 = 1.

• note: ensemble average quantities denoted by <>’s.

– …the expected result, from probability considerations.

Modeling Structural Transitions in

Biopolymers

The 2-state system is conceptually simple.

– Adopting a 2-state model for a biopolymer:

• Process described as an all-or-none transition;

– Then, weights of only two states are considered;

• Useful for assessing the total Keq of formation.

– However: yields no information about folding intermediates.

• e.g., partially folded states.

• We need a more complete description

– much more complicated.

Simplification: Focus on 2o structure

– limits the problem to transitions b/w well-defined states:

• For polypeptides:

– between a random coil and an α-helix.

– alternatively, between an α-helix and a β-strand.

• For polynucleotides:

– between a pair of random coils and a double-strand (helix).

– alternatively, b/w a B-helix and an A- or Z-helix.

Generalized Two-State Modeling

Each residue in a biopolymer may assume many states.

– e.g., ranging from fully ‘helical’ to fully ‘coil’.

Simplification: residue-level, 2-conformation model.

– 2o structure formation all-or-none for each residue.

• DNA: each base-pair either stacked or unstacked.

– …or H-bonded or non-H-bonded, in our simple treatment.

• Polypeptide: each residue either H-bonded or free.

Again, we consider the overall transition:

– from a reference or starting state (A) to a new state, (B).

But, each residue has either the properties of A or B.

• i.e., is in state a or b.

– Limiting states:

• A = …aaaaaa… (all residues have the properties of A)

• B = …bbbbbb… (all residues have the properties of B)

– Many ‘intermediate’ states: …aaabbaa…

Model for an N-residue Chain

Assign a weight to each residue, based on

conformation:

– a: assign weight, ωa = 1 (the residue reference state).

– b: assign weight, ωb = s.

Also, residue transitions may be ‘cooperative’.

– assign a nucleation penalty, σ½ to each ab interface.

– may also be assigned to b’s at chain ends (model-dependent)

Total statistical weight of each chain state…

– then given by the product of all residue weights.

– States with identical weights classified as degenerate…

• grouped into a single, macroscopically-observable chain state.

There are 3 cases:

– which depend on the size of σ, relative to s:

• Here, σ models process ‘cooperativity’.

Model 1: All-or-None

Transition from A to B, length N polymer.

– Reference State = State A (all a’s).

– Each residue has properties of state A or B.

• ωa = [a]/[a] = 1, ωb = [b]/[a] = s.

• here…micro-equilibrium contants.

– residue transitions totally cooperative (σ = 0).

• but no σ½ assigned to b’s at chain ends.

• residues change in unison…

– e.g., for …aabaa…, weight = …(1)2(σs)(1)2…= 0.

Result:

– only homogenous chains have nonzero weight.

– Let ‘j’ denote the number of b’s.

– Only 2 occupied states, each with degeneracy

of 1:

• State A (j=0)…ωo = 1.

• State B (j=N)…ωN = sN.

Estimating PA and PB.

Both states A and B are unique:

– degeneracy, g0 = gN = 1.

Partition Function:

• Q = 1 + sN.

Probability of observing states A and B:

– estimated by a ratio of statistical weights:

• PA = ωA/Q = 1/(1+sN).

• PB = ωB/Q = sN/(1+sN).

– equilibrium probabilities.

Physical interpretation of parameter s:

• s = exp[- ∆Goab / RT].

• ∆Goab = Gob - Goa is the standard free energy

– of residue conversion from a to b.

Ensemble Average Fraction of b’s

Ensemble averages are also obtainable from Q…

– by constructing a weighted average.

Example: Mean Fraction of b’s

– Denoted by <Pb>.

– j and fj = j/N are the number and fraction of b’s in state j.

– <Pb> is the weighted average of fj:

Parameter s:

– related to mean free energy of residue conversion, ∆Goab,

by the Gibbs factor:

s = exp[- ∆Goab / RT].

• when ∆Goab < 0, <Pb> is greater than ½.

• when ∆Goab = 0, <Pb> = ½, as expected.

Utility of the All-or-None Model

Advantages:

– conceptually simple.

– correctly estimates relative occupancies of A, B.

– provides estimates of the gross details of the transition.

Disadvantages:

– neglects the occupancy of intermediate conformations…

• occupancies of other states unmodeled.

• Thus, absolute occupancies of A, B generally overestimated.

– structural details of the transition unavailable.

• e.g., misses ‘sub’-transitions.

Primarily uses:

– developing an approximate picture of the transition.

– estimation of overall, or ‘bulk’ equilibrium constants (Keq).

Model 2: Non-Cooperative

Transition from A to B, length N polymer.

– Reference state = state A.

– again, residues have properties of A or B.

• ωa = [a]/[a] = 1, ωb = [b]/[a] = s.

– residue transitions non-cooperative (σ = 1):

• each residue converts independently.

Result: Biopolymer has N+1 states…

– chains with equal j values are equivalent;

• have the same weight, sj.

• grouped into a single chain ‘state’, j.

– states then enumerated by j:

• N + 1 states…j = 0,…, N.

– Weight of state j:

• ωj = gj sj = N!/[j!(N-j)!] * sj.

The Partition Function, Q

Degeneracy of state j:

– Given by: gj = N! / [j!(N-j)!] = C(N,j).

• …the binomial coefficient;

• number of ways of placing j balls in N boxes.

Partition Function:

– equal to the sum over all states:

Q = Σj sj N!/[j!(N-j)!].

• but this has the form of a binomial expansion, which

reduces to:

Q = (1 + s)N…

– e.g.; (N = 4): Q = 1 + 4s + 6s2 + 4s3 + s4 = (s+1)4.

The Propagation Parameter, s

In the non-cooperative model, the propagation

parameter:

– expresses the probability that any residue converts from

a to b;

equilibria…

• i.e., a series of 1-residue transitions;

• Thus, s is the equilibrium constant for each micro-transition.

Equilibrium Occupancy of State j

Probability of observing state j:

– i.e., one of gj physically distinct, equivalent chains…

• with j b’s;

• denoted by Pj.

– again, given by a ratio of statistical weights:

• Pj = ωj/Q

sj/(1 + s)N ; C(N,j) = N! / [j!(N-j)!]

= C(N,j)

For the special case in which s = 1,

– We note that, ∆Goab = 0.

– Residue occupancies are random…since ωa = ωb = 1;

• Each residue executes a random walk.

– Then, the most likely state = most degenerate state.

• C(N,j) is maximum for state, j = N/2.

– Example: For N = 4…most likely state is j = 2.

• degeneracy, g2 = C(4,2) = 6.

Ensemble Average Fraction of b’s

• By constructing a weighted average.

– Example: Mean Fraction of b’s :

• Denoted by <Pb>.

• fj = j/N = fraction of b’s in state j.

<Pb> = Σj fjωj/Q = Σj (j/N) C(N,j) sj /(1+s)N

= s/(1+s)

– The mean Fraction of a’s is then:

<Pa> = 1 - <Pb> = 1/(1+s).

• so that…

<Pb>/ <Pa> = s, as we expect.

Utility of the Non-Cooperative

Model

Since each step is independent, this model…

– may be used to describe a random walk.

– As well as non-cooperative binding of multiple ligands:

• e.g., proteins with multiple, independent active sites.

Most Biopolymer 2o structure transitions:

– exhibit an intermediate level of cooperativity…

– neither the all-or-none, nor non-cooperative models suitable.

• more sophisticated model required.

Modeling Intermediate Cooperativity

Model…Transition from A to B, length N polymer.

– a and b weighted: ωa = 1, ωb = s.

– however…transitions are cooperative (1 > σ > 0).

• σ½ assigned to each ‘ba’ interface, and each terminal b.

– degree of cooperativity: relative size of s and σ.

• σ = 1…non-cooperative model.

• σ << s…all-or-none model (more accurate: s 0).

• σ often called the ‘cooperativity parameter’.

Now, we will have many distinct states:

– not all chains with j b’s are equivalent…

– e.g., consider the 2 chains, below (each w/ 2 b’s):

• …aabbaaa… ω = σ s2.

• …aababaa… ω = σ2s2. Not equivalent!

– The general model (with all states) is very complex…

Model 3: Statistical Zipper Model

For biopolymers, generally 0 < σ << 1…

– results in a zipper-like transition.

Two types of residue transitions:

– initiation: formation of an isolated b;

• also called ‘nucleation’...

• This is high energy (σ << 1)…difficult.

• σ often called the initiation parameter.

– propagation: formation of ‘neighboring’ b.

• low energy for T < Tm (i.e., s > 1)...easy.

• s called the ‘propagation parameter’.

Simplification: The Zipper Model.

– chains with more than 1 isolated b neglected.

• e.g., …aababaa… (hard to form!)

– After a single nucleation…

• Transition expands in a Zipper-like fashion.

– Chains with j consecutive b’s equivalent;

• grouped into a single ‘state’, j.

The Partition Function

Again, we have N+1 states…

– each denoted by the value of j.

• where j denotes the number of b’s in the chain.

Each state has much smaller degeneracy:

– Given by: gj = N-j+1; for N >= j > 0.

• Number of ways of placing a string of j b’s in N positions.

• Here, go = 1 (treated as an exception).

Partition Function:

– sum of the weights of all states.

Q = 1 + Σj>1 ωj

= 1 + σ Σ j>1 (N - j + 1) sj,

Ensemble Average Fraction of b’s

Ensemble averages again obtainable from Q.

– by constructing a weighted average.

Estimating the Mean Fraction of b’s (< Pb >):

– j and fj are the number, fraction of b’s in state j:

• we have: fj = j/N.

– Weighted average of fj yields <Pb>:

– polymer length contributes to propagation, but not initiation.

• s, σ thus experimentally resolved by studying <Pb> vs. N.

Degree of Cooperativity

Determined by the size of σ:

– sharpness of the transition increases with decreasing σ.

• remember that s varies with T:

s = exp[-∆Goab/RT]

• σ often called the ‘cooperativity parameter’.

Limiting cases correspond to our other models:

– Case I - if σ << s:

• transition highly cooperative…

• approaches our all-or-none

model.

– Case II - if σ = 1,

• transition is not cooperative…

• reduces to our non-cooperative

model.

Applicability of the Zipper Model

Applicable to a wide range of biopolymer transitions:

– formation of multi-meric complexes by subunit assembly.

• e.g., viral coat assembly.

– formation of regular structures along a biopolymer chain.

• transition of a coil to an α-helix (polypeptide folding);

• transition of a B-helix to a pair of ssDNA coils (DNA melting);

– The reverse process.

• the B- to Z-helix transition (DNA).

Application requires assigning physical meanings to σ

and s.

– this allows the definition of each state:

• in terms of an experimentally-meaningful statistical weight.

– thus, allows estimation of the system’s partition function (Q).

The Nucleation Parameter, σ

Again, σ determines process cooperativity.

– non-cooperative processes:

• should be modeled with σ ~ 1.

– processes which exhibit a higher cooperativity:

• modeled with smaller values of σ.

σ intrinsic to each type of biopolymer:

– different values for different biopolymers…

• even if the transition appears to be similar.

– Also specific to the type of transition:

• e.g., α-helix/coil, α-helix/β-strand, etc…

σ independent of Temperature and Length:

• Often also considered roughly independent of sequence.

– Once determined for a given polymer and transition…

• will be equally applicable to any instance.

The Propagation Parameter, s

Dependent on the specific interactions:

– that stabilize or destabilize a and b.

– Specifically, s = exp(-∆Goab/RT)

• where ∆Goab = Gob- Goa.

– since ∆Goab = ∆Hoab - T ∆Soab, s consists of both:

• T-dependent component… exp(-∆Hoab/RT);

• T-independent component…exp(∆Soab/R).

– both of which can determined experimentally…

• or, if desired, can be estimated by simulation.

Forward

In this lecture, we have described:

– the basic ideas behind statistical thermodynamic modeling:

• as applied to state transitions of a polymer chain.

– the Zipper model approximation:

• and its dependence on σ…

• as well as its two limiting cases:

– the all-or-none model (σ << s).

– and the non-cooperative model (σ = 1).

In the next 2 lectures:

– we focus on a limited set of biopolymer applications:

• the coil to α-helix transition of polypeptides.

• the melting transition of the DNA B-helix.

• the B-DNA to Z-DNA transition.

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