Details of Grant 

EPSRC Reference:	EP/G025746/1
Title:	Phototriggered polypeptide unfolding dynamics: a nonadiabatic multiscale simulation study
Principal Investigator:	Doltsinis, Professor NL
Other Investigators:
Researcher Co-Investigators:
Project Partners:
Department:	Physics
Organisation:	Kings College London
Scheme:	First Grant Scheme
Starts:	01 October 2009	Ends:	17 November 2013	Value (£):	270,185
EPSRC Research Topic Classifications:	Chemical Biology Protein folding / misfolding
EPSRC Industrial Sector Classifications:	No relevance to Underpinning Sectors
Related Grants:
Panel History:	Panel Date Panel Name Outcome 19 Nov 2008 Chemistry Prioritisation Panel November Announced
Summary on Grant Application Form
Protein folding and unfolding dynamics is of fundamental importance in biology as it regulates the biological activity of proteins. To shed light on the dynamical conformational changes which convert a polypeptide chain into a three-dimensional protein structure has been the objective of a vast number of experimental and theoretical studies. Experimental studies of protein folding or unfolding require a triggering event initiating the conformational dynamics. Traditional stopped-flow mixing techniques have a time resolution of a few milliseconds and are thus not able to elucidate important fast folding processes. The latter can be conveniently investigated using recently developed ultrafast phototriggers. The basic idea is to synthesize cyclic polypeptides containing a photocleavable disulphide, S-S, bridge. In this pro ject, we focus on the beta-turn cyclo-(Boc-Cys-Pro-Aib-Cys-OMe) tetrapeptide studied recently by transient 2D infrared spectroscopy. To interpret spectroscopic results and to gain detailed insight into the mechanisms governing S-S photocleavage into two S radicals, polypeptide unfolding, and recombination of the S radicals on the atomistic and electronic structure level theoretical investigations are indispensable. So far only classical molecular dynamics (MD) simulations using empirical interaction potentials have been performed. Classical MD is unable to deal with the crucial initial step, photocleavage, as it does not treat electrons explicitly. Moreover, classical MD precludes the breaking and formation of chemical bonds. Thus the important S-S cleavage and recombination as well as any reactions of the S radicals with the solvent cannot be described.A realistic theoretical treatment of the phototriggered unfolding of the polypeptide requires a hierarchy of computational methods. The initial ultrafast photodissociation of the S-S bond requires a nonadiabatic ab initio molecular dynamics (na-AIMD) simulation method, i.e. a technique that goes beyond the usual Born-Oppenheimer approximation. Such an approach has been developed recently by the Investigator. This two-state approach is based on density functional theory and couples the Kohn-Sham electronic ground state, S0, and the restricted open-shell Kohn-Sham (ROKS) first excited singlet state, S1, via a surface hopping scheme. While this na-AIMD method can be applied to study the sub-picosecond disulphide bridgephotocleavage of the tetrapeptide in the gas phase, a full na-AIMD simulation in solutionsystem is computationally unfeasible. The limitation can be overcome by resorting to a nonadiabatic hybrid quantum-classical QM/MM (na-QM/MM) approach in which only the photoactive -S-S- unit is treated quantum-mechanically and the remaining atoms of the peptide as well as the solvent environment are treated classically. Such a na-QM/MM method has been implemented in our group very recently; it combines our na-AIMD method with the QM/MM interface between the CPMD and GROMOS software packages developed by Laio et al..While QM/MM techniques can overcome the limitations of AIMD with regards to system size, their typical simulation length is still of the order of picoseconds and thus too short to study the slow conformational changes of the polypeptide on the nanosecond time scale. After the photocleavage is completed and the system has relaxed to the electronic ground state, it is therefore necessary switch to a purely classical force field, MM, description. However, the MM description precludes an important aspect of the peptide dynamics, namely the recombination of the two sulphur radicals to reform a S-S bridge. To take this possibility into account, one has to switch back to the AIMD or QM/MM model below a certain S-S cutoff distance. An adaptive multiscale code of that sort which smoothly and automatically switches between the QM and MM representations is currently not in place and shall be implemented within this project.
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