BioPHYSICAL chemistry

final fold. Two general interactions influence the intermediate state. The

overall globular shape reflects the sequestering of hydrophobic residues

in the interior away from water molecules that minimize the unfavorable

hydrophobic interactions. The presence of secondary structures, in particular

αhelices, reflects the formation of hydrogen bonds among neighboring

amino acid residues. The intermediate state effectively provides the tem-

plate for the subsequent formation of the fully folded conformation.

The prediction and design of the three-dimensional structures of proteins

provides the opportunity to test the accuracy of our understanding of the

interactions that underlie protein folding. Many of these

approaches have focused on the interactions involved

in the formation of the intermediate state, hydrophobic

and hydrogen-bonding interactions, and packing inter-

actions. Whereas the prediction algorithms identify the

lowest-energy state of a given sequence, and in some cases

an initial model, the design of a fold must involve the

determination of the sequence with the lowest energy

for the given structure (Figure 13.15). The successful

design of new proteins has demonstrated the power of

this methodology. The sequence with the lowest energy,

computed for the fold of a small naturally occurring pro-

tein called a zinc finger, was found to adopt a structure

that was found by NMR (Chapter 16) to be highly

homologous to the starting sequence (Dahiyat & Mayo

1997). By iterating between the design and prediction

algorithms, a new protein was designed that had a novel

topology which proved to be very stable (Figure 13.16).

Figure 13.15Algorithm for protein design.
(a) Protein prediction and design are related
problems that both make use of computer
algorithms of protein interactions.
(b) Similarity of flexible backbone design
and structure prediction. Modified from
Schueler-Furman et al. (2005).

288 PART 2 QUANTUM MECHANICS AND SPECTROSCOPY

(a)

Prediction:
Find lowest
energy
structure
for fixed
sequence

Design:

Find lowest

energy

sequence

for fixed

structure

Sequence

Structure

Model of energetics

of inter- and

intramolecular

interactions

Randomly perturb backbone and/or rigid body

degrees of freedom

Gradient-based local minimization of energy

with respect to all degrees of freedom

Discrete optimization of side-chain rotamers

Design:

All rotamers for

all amino acids

(b)

Prediction: Accept?

All rotamers for native

amino acids

C

N

Figure 13.16
Three-dimensional
structure of a novel
design protein.
Modified from
Kuhlman et al.
(2003).