atoms from moving beyond realistic bond distances and angles. For
refinement of X-ray data, the positions are also adjusted to agree with
the diffraction data, by effectively adjusting the position of each atom
so that it is located in a position of local electron density. For NMR
data, distance constraints can be similarly imposed. Then the process
repeats, typically in 100 increments for refinement and much longer
for dynamics. As the trajectory progresses, the protein changes from an
unfolded configuration to a globular structure (Figure 13.14).
In a molecular-dynamics calculation, a very high temperature is poised
in order to provide enough energy to overcome local barriers. After a period
involving hundreds to thousands of steps the temperature is cooled, allow-
ing the structure to approach a true equilibrium. The temperatures are
not intended to be realistic. For example, a temperature of 3000 K may
be used, but this only provides a parameter to adjust the overall allowed
degree of motion. Once the dynamics have been completed, the tem-
perature is adjusted to 295 K, either instantly or very slowly. During
refinement, in order to avoid the possibility of incorrect motion due to
incorrect assignment of the charges of the amino acid side chains, the
electrostatic term is not normally used.
In addition to being of use in refining structural models of proteins and
probing their dynamics, computer models allow scientists to address one of
the outstanding questions in structural biology, namely how the informa-
tion necessary for proper folding is stored in the primary sequence of a
protein (Daggett & Fersht 2003; Kuhlman et al. 2003; Clark 2004; Onuchic
& Wolynes 2004; Lindorff-Larsen et al. 2005; Schueler-Furman et al. 2005).
Proteins are thought to fold into intermediate states before reaching their
Figure 13.14The folding trajectory for a protein from an unfolded to a
folded configuration, (a) to (d). Modified from Onuchic and Wolynes (2004).
CHAPTER 13 CHEMICAL BONDS AND PROTEIN INTERACTIONS 287
0 1 0203040Contact energyIntegration time step (x10^6 )τ 1
τ 2(a)(b)(c)(d)