Sequencing of folding events in Go-type proteins

Abstract

We have studied folding mechanisms of three small globular proteins: crambin (CRN), chymotrypsin inhibitor 2 (CI2) and the fyn Src Homology 3 domain (SH3) which are modelled by a Go-like Hamiltonian with the Lennard-Jones interactions. It is shown that folding is dominated by a welldefined sequencing of events as determined by establishment of particular contacts. The order of events depends primarily on the geometry of the native state. Variations in temperature, coupling strengths and viscosity affect the sequencing scenarios to a rather small extent. The sequencing is strongly correlated with the distance of the contacting aminoacids along the sequence. Thus α-helices get established first. Crambin is found to behave like a single-route folder, whereas in CI2 and SH3 the folding trajectories are more diversified. The folding scenarios for CI2 and SH3 are consistent with experimental studies of their transition states.

Protein folding in a force clamp

“…This choice of γ corresponds to a situation in which the inertial effects are small 6 but the damping action is not yet as strong as in water. The more realistic damping is stronger by a factor of order 25 which extends the effective time scales by the same factor since the dependence of the folding times on γ is linear 6 . The equations of motion are solved by a fifth order predictor-corrector scheme.…”

“…The molecular dynamics time evolution is governed by the time unit τ = mσ 2 /ǫ ≈ 3ps where m is the average mass of the amino acids. For our model of ubiquitin, the reduced temperature of melting is 0.23 and that of optimal folding 0.28 which indicates good unfrustrated kinetics and two-state folding behavior 6 . In an unfolded state there are no contacts and folding means increasing the number of contacts that get established.…”

“…The kinetics of folding can be quantified with the use of the so called scenario diagrams 6,25 in which one plots an average time to establish a contact, t c , against the contact order, i.e. against the sequential distance, j − i, between the amino acids that form a native contact.…”

Computing the transition state populations in simple protein models

“…The energy landscape is not yet known for atomistic models but it is possible to explore the landscape using a Go model. Go models have proven useful in earlier folding kinetics studies, 19,20 and their results were comparable to those obtained with full models. 19 -21 Conformational transitions are assigned rate constants based on intramolecular energy barriers and friction.…”

Folding of proteins in Go models with angular interactions

“…Clearly, there are many ways of accomplishing this but they are expected to be physically similar. Our approach is outlined in references [19,20] with the updated details given in [13]. Briefly, the amino acids are represented by point particles of mass m located at the positions of the C α atoms.…”