Dr Emanuele Paci
Computational chemistry, biological physics, statistical mechanics, computational design of bioinspired functional assemblies
Most of my research in the past decade has been devoted to advance understanding of properties of macromolecules in biological contexts, by using computer simulations to establish a relation between physical models and experimental measurements. One unique property of biological polymers such as proteins and RNA is their ability to populate a state characterised by a precisely defined conformation, unlike any man-made polymers. Protein folding is one of the major focuses of our recent research, with a particular interest to the relation between folded structure, unfolding pathway and mechanical properties. Our theoretical and computational research in this field has had impact on the way experiments are performed and interpreted, while mechanical response is increasingly recognised as an essential part of many biological processes.
More recently we have turned our interests to the growth of bacterial pili, rational design of symmetric protein complexes such as capsids (with B. Turnbull), analysis of time resolved X-ray spectroscopy data (with A. Pearson), determination of structure and dynamics of macromolecular compounds from cryo-EM (with S. Muench) and hydrogen-exchange mass spectroscopy experiments (with R. Tuma).Current major projects include:
- Rational tools for predicting molecular interactions
- Molecular biomechanics and adhesion
- development of computational methods for structural determination from
- Computational methods for structure determination from sparse data
Most of my research in the past decade has been devoted to advance understanding of properties of macromolecules in biological contexts, by using computer simulations to establish a relation between physical models and experimental measurements. One unique property of biological polymers such as proteins and RNA is their ability to populate a state characterised by a precisely defined conformation, unlike any man-made polymers. Protein folding is one of the major focuses of our recent research, with a particular interest to the relation between folded structure, unfolding pathway and mechanical properties. Our theoretical and computational research in this field has had impact on the way experiments are performed and interpreted, while mechanical response is increasingly recognised as an essential part of many biological processes. A number of reviews and book chapters on our contribution to the field are available (Yew and Paci, (2012) Comprehensive Biophysics, Volume 3 doi:10.1016/B978-0-12-374920-8.00308-8, Yew et al (2012) Single-Molecule Biophysics: Experiment and Theory, Advances in Chemical Physics, Vol 146).
Monteiro, Petnga & Paci, PLoS One (2013). Bacterial pilogenesis is a remarkable example of biological non-templated self-assembly where a small number of different building blocks are arranged in a specific order resulting in a macroscopic hair-like fiber containing up to thousands copies of protein subunits. Advanced experimental techniques have been used to understand pilus growth. While structures protein building blocks before and after the elementary polymerisation are known, such information does not explain how, and how fast, the growth occurs. We have shown that correlated dynamics is a major determinant of the growth of pili as diverse as P-pilus (in the picture) and type 1 pilus from E.coli (Verger et al., Structure (2008), Rose et al., Proc. Natl. Acad. Sci. USA (2008)) and Saf pilus from Salmonella (Rose et al., J. Mol. Biol. (2008)).
Settanni et al., PLoS Computational Biology (2013). Ankyrin repeat proteins are elastic materials that unfold and refold sequentially, repeat by repeat, under force. Atomistic molecular dynamics show that the bounding its natural partner greatly increases the resistance of the 7-ankyrin-repeat oncoprotein Gankyrin to mechanical stress. The effect is specific to those repeats of Gankyrin directly in contact with S6-C, and the mechanical ‘hot spots’ of the interaction map to the same repeats as the thermodynamic hot spots. A consequence of stepwise nature of unfolding and the localized nature of ligand binding is that it impacts on all aspects of the protein’s mechanical behavior, including the order of repeat unfolding, the diversity of unfolding pathways accessed, the nature of partially unfolded intermediates, the forces required and the work transferred to the system to unfold the whole protein and its parts. Stepwise unfolding thus provides the means to buffer repeat proteins and their binding partners from mechanical stress in the cell. Our results illustrate how ligand binding can control the mechanical response of proteins and point to a cellular mechano-switching mechanism whereby binding between two partner macromolecules is regulated by mechanical stress.
Forman et al. Structure (2009). Experimental observation has led to the commonly held view that native state protein topology is the principle determinant of mechanical strength. However, the PKD domains of polycystin-1 challenge this assumption: they are stronger than predicted from their native structure. Molecular dynamics simulations suggest that force induces rearrangement to an intermediate structure, with nonnative hydrogen bonds, that resists unfolding. We tested this hypothesis directly by introducing mutations designed to prevent formation of these nonnative inter- actions and found that these mutations, which only moderately destabilize the native state, reduce the mechanical stability dramatically. Non-native interactions impart significant mechanical stability, necessary for the mechanosensor function of polycystin-1. Remarkably, such non- native interactions result from force-induced conformational change: this is the first protein shown to be strengthened by the application of force.
Bellucci et al. PLoS One (2013). Neuronal calcium sensor-1 (NCS-1) is a protein able to trigger signal transduction processes by binding a large number of substrates and re-shaping its structure depending on the environmental conditions. The X-ray crystal structure of the unmyristoilated NCS-1 shows a large solvent-exposed hydrophobic crevice (HC), this HC is partially occupied by the C-terminal tail and thus elusive to the surrounding solvent. Simulation showed that the native state of NCS-1 is one, and the differences observed in crystal and the solution structures are artifacts. Yet interesting artifacts: relaxation to a state independent of the initial structure, in which the C-terminal tail occupies the HC. We suggest that the C-terminal tail, which is disordered in the NMR structure, shields the HC binding pocket and modulates the affinity of NCS-1 for its natural targets. A combination of optical tweezers and simulation (Hedairsson et al., Submitted) show that the folding mechanism of NCS-1 involves two intermediates and cooperativity between the domains.
Associate Professor (Leeds) 2007-present
"Laurea" (La Sapienza", Rome) "Doctorat" (Universi
Postdoc (Oxford) 1996-2001
Oberassistent (Zurich) 2001-2004
Astbury Building 8.106
School of Molecular and Cellular Biology
0113 343 3806
Effects of Ligand Binding on the Mechanical Properties of Ankyrin Repeat Protein Gankyrin Author(s): Settanni, Giovanni; Serquera, David; Marszalek, Piotr E.; et al. Source: PLoS Computational Biology Volume: 9 Issue: 1 Published: JAN 2013
Using Models to Design New Bioinspired Materials Author(s): Paci, Emanuele Source: Biophysical Journal Volume: 103 Issue: 9 Pages: 1814-1815 Published: NOV 7 2012
Direct evidence of the multidimensionality of the free-energy landscapes of proteins revealed by mechanical probes Author(s): Yew, ZT; Schlierf, M; Rief, M; et al. Source: Physical Review E Volume: 81 Issue: 3 Published: 2010
Non-Native Interactions Are Critical for Mechanical Strength in PKD Domains Author(s): Forman, J. R.; Yew, Z. T.; Qamar, S.; et al. Source: Structure Volume: 17 Issue: 12 Pages: 1582-1590 Published: 2009