[Todos] Miercoles 28 de marzo - 13 hs - Seminarios DQIAQF - INQUIMAE

[andrea en qi.fcen.uba.ar]

Seminarios DQIAQF - INQUIMAE, Miercoles 28 de marzo - 13 hs.

Aula de Seminarios INQUIMAE - DQIAQF
Facultad de Ciencias Exactas y Naturales
Ciudad Universitaria - Pab. 2  -  Piso 3

The conformational basis of enzyme kinetics

S. Kashif Sadiq

Universitat Pompeu Fabra, Barcelona

Many proteins, exploit transitions between several molecular conformations
to achieve their various functions.  Enzymes in particular need to bind
substrate, stabilize the transition state and release product, all of
which may be facilitated by adopting different conformations.

To better understand the role of conformational flexibility in affecting
enzyme interactions requires a quantitative energetic and kinetic
characterization of the conformational landscape often with an
atomic-level detail of description at the relevant timescale of the
process. Unfortunately, no experimental method yet exists that can probe
the conformational dynamics at relevant timescales, whilst retaining the
detailed atomic-level information.

I will discuss how a combination of high-throughput all-atom molecular
dynamics (MD) simulations coupled with the use of transition path theory
can be used to build Markov state models (MSM) that elucidate the
conformational kinetics of proteins at biologically interesting
timescales.
I will focus on the conformational flexibility of HIV-1 protease, the
enzyme of HIV responsible for cleavage of viral polyprotein precursors
that leads to viral maturation and infectivity.  One fascinating aspect of
this enzyme is that it autocatalyzes its own release from within the viral
polyproteins that it cleaves. I will discuss how this is achieved by an
intramolecular mechanism for which the rate can be calculated using the
MSM methodology and for which conformational transitions in the enzyme
play a crucial role.
Finally, I will address the need for a multiscale physical framework that
couples processes occurring at different spatiotemporal scales, in order
to achieve a more complete understanding of enzyme kinetics and the
biological processes that they mediate. Such a framework should provide
the basis to link not only electronic structure information with molecular
conformational kinetic processes but also the latter with higher scale
reaction kinetic schemes from which the evolution of macroscopic
biological processes can be predicted.