The curious case of A31P, a topology-switching mutant of the Repressor of Primer protein : A molecular dynamics study of its folding and misfolding
arxiv(2024)
摘要
The effect of mutations on protein structures is usually rather localized and
minor. Finding a mutation that can single-handedly change the fold and/or
topology of a protein structure is a rare exception. The A31P mutant of the
homodimeric Repressor of Primer (Rop) protein is one such exception: This
single mutation -and as demonstrated by two independent crystal structure
determinations- can convert the canonical (left-handed/all-antiparallel)
4-alpha-helical bundle of Rop, to a new form (right-handed/mixed parallel and
antiparallel bundle) displaying a previously unobserved 'bisecting U' topology.
The main problem with understanding the dramatic effect of this mutation on the
folding of Rop is to understand its very existence : Most computational methods
appear to agree that the mutation should have had no appreciable effect, with
the majority of energy minimization methods and protein structure prediction
protocols indicating that this mutation is fully consistent with the native Rop
structure, requiring only a local and minor change at the mutation site. Here
we use two long (10 us each) molecular dynamics simulations to compare the
stability and dynamics of the native Rop versus a hypothetical structure that
is identical with the native Rop but is carrying this single Alanine-31 to
Proline mutation. Comparative analysis of the two trajectories convincingly
shows that in contrast to the indications from energy minimization -but in
agreement with the experimental data-, this hypothetical native-like A31P
structure is unstable, with its turn regions almost completely unfolding, even
under the relatively mild 320K NpT simulations that we have used for this
study. We discuss the implication of these findings for the folding of the A31P
mutant, especially with respect to the proposed model of a double-funneled
energy landscape.
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