BioExcel’s webinar series continues with a special edition featuring student speakers who were awarded poster prizes at the BioExcel Summer School 2020. Read along to find out more about our speakers and their research.

Date: 15th September, 2020
Time: 15:00 CEST / 14:00 BST

Carla Calvó-Tusell

Carla is currently a PhD student at CompBioLab research group at the Institute of Computational Chemistry and Catalysis at the University of Girona under the supervision of Dr. Marc Garcia-Borràs and Prof. Sílvia Osuna. In 2019, she started a PhD thesis focused on developing new computational enzyme evolution protocols for designing new enzymes. Her thesis is focused on exploring enzyme conformational dynamics through computational molecular dynamics-based approaches including enhanced sampling techniques and correlation-based tools in combination with experimental validation to rationally predict mutations to engineer novel enzyme catalysts. Carla also works in the characterization of allosteric activation mechanisms using simulation techniques to describe long timescale motions. She is also responsible for performing experimental characterization of computationally designed variants.

Twitter: @ccalvotusell @IQCCUdG @univgirona

Unraveling the millisecond allosteric activation of Imidazole Glycerol Phosphate Synthase (IGPS)

Allostery is an intrinsic property of proteins generally described as the process by which the effect of binding at one site is transmitted to another, often distal, functional site, allowing for activity or function regulation. Exploring the mechanisms of allosteric regulation is important to understand biological processes such as enzyme catalysis or cell signaling. Computational methods are used to study allostery, but obtaining enough conformational sampling to completely characterize allosteric events represents a challenge for current simulation techniques. Imidazole Glycerol Phosphate Synthase (IGPS) is a heterodimeric enzyme complex widely used as a model to study allosteric regulation between subunits. Previous studies based on NMR experiments reported that the allosteric activation of IGPS takes place in the millisecond timescale. However, the complete activation mechanism of IGPS has not been yet characterized.

In this work, the millisecond allosteric activation mechanism of IGPS is unraveled stepwise by a combination of simulation techniques. First, nanosecond to microsecond motions that initiate the allosteric signal transmission are deciphered by means of conventional Molecular Dynamics (cMD). Second, accelerated Molecular Dynamics (aMD) is used to sample events that occur in the microsecond to millisecond timescale, including the complete reconstruction of substrate binding process and the allosteric activation of IGPS (characterized by the formation of an oxyanion hole). Third, the active state obtained with aMD is used to select the proper reaction coordinate to reconstruct the free energy landscape of the activation process by metadynamics. Finally, the allosteric communication pathway is traced through key residues for IGPS function and allostery using Shortest Path Map. In summary, we have been able to characterize the activation mechanism of IGPS by applying a computational protocol designed to describe and characterize complex long timescale motions.

Andrea Saltalamacchia

Andrea is a PhD student at SISSA in Triest under the supervision of Dr. Alessandra Magistrato. He is a computational biologist that applies MD simulations and statistical analyses to different biological systems in splicing. His current work focuses on simulations aimed at studying the recognition of splicing sites and signal communication in the spliceosome complex.

Decrypting the Information Exchange Pathways across the Spliceosome Machinery

Intron splicing of a nascent mRNA transcript by spliceosome (SPL) is a hallmark of gene regulation in eukaryotes. SPL is a majestic molecular machine composed of an entangled network of proteins and RNAs that meticulously promotes intron splicing through the formation of eight intermediate complexes. Cross-communication among the critical distal proteins of the SPL assembly is pivotal for fast and accurate directing of the compositional and conformational readjustments necessary to achieve high splicing fidelity. Here, molecular dynamics (MD) simulations of an 800000 atom model of SPL C complex from yeast Saccharomyces cerevisiae and community network analysis enabled us to decrypt the complexity of this huge molecular machine, by identifying the key channels of information transfer across long distances separating key protein components.

The reported study represents an unprecedented attempt in dissecting cross-communication pathways within one of the most complex machines of eukaryotic cells, supporting the critical role of Clf1 and Cwc2 splicing cofactors and specific domains of the Prp8 protein as signal conveyors for pre-mRNA maturation. Our findings provide fundamental advances into mechanistic aspects of SPL, providing a conceptual basis for controlling the SPL via small-molecule modulators able to tackle splicing-associated diseases by altering/obstructing information-exchange paths.

Bia Fonseca 

Bia is currently pursuing her PhD at the University of Copenhagen. Her current professional interests include the use of analytical techniques to better understand the material and anthropological aspects of works of art and historical objects and the development of new non-invasive state of the art analytical technology, particularly using combined spectroscopic techniques. Moreover, starting with her PhD studying degradation patterns of proteins, she aims to apply Computational Chemistry to problems encountered in Heritage Science, a field which still has limited access to computational methods.

The Role of Water in Protein Decay

Proteins are more complex to study than DNA because of their greater organizational and structural variation. For this reason, there is little information on patterns of protein decay. Current methods to authenticate ancient proteins are faulty due to difference in environmental conditions samples are subject to, which may lead to erroneous dating. To be able to more confidently date ancient proteins and further develop new or existing methods to be more precise, it is paramount to have a clear picture of the patterns involved in the different processes of protein decay. Hydrolysis plays a big part in the breakdown of proteins and a recent paper by the group has highlighted remarkable preservation in fossil tooth enamel. The most plausible explanation for the difference in preservation is that fewer water molecules are entrapped with the protein in enamel, being preserved by, to an extent, dehydration. Therefore, it is essential to explore the role of water in degradation and to what extent solvation shells structure water. What happens when the water threshold begins to limit the number of water molecules around each residue? What is the role of the mineral surface in limiting hydrolysis? Using the Amber14SB forcefield for proteins and SPC/E water in the Gromacs 2020 software, we perform molecular dynamics simulations of milk proteins peptides that have been found to survive in deep time, in order to better understand entropy effects of solvation dynamics both of the protein in bulk water and attached to a mineral surface.