Search

In recent years, the application of Molecular Dynamic (MD) simulations has become a widespread tool in biological and medical research. This type of simulations provide atomistic information and estimate thermodynamics and kinetics event associated with physical and biological processes. Due to improvement in simulation speed, accuracy and accessibility, MD simulations have become a routine protocol applied in different subjects, such as the modelling of biomolecules or during the drug discovery process. However, it is not always possible to properly sample biological processes that happen in long-timescale through simple MD. For this reason, an important effort has been put to provide new methodologies in MD, to accelerate the timescale of simulations, and to obtain results in agreement with experimental data. This thesis contributes to these efforts by presenting a new method to sample rare events and by understanding biological mechanisms. I start by presenting a new method to predict the free energy of protein-ligand unbinding and demonstrate the efficacy of the method by applying it to a system with experimental kinetic data. Furthermore, I describe what information MD simulations can provide by applying it to different biological systems. Specifically, I provide insights into the inhibition mechanism of integrase inhibitors used for the treatment of HIV. I then unravel the mechanism behind the formation of the D-Ala peptide through the D-Ala-D-Ala ligase, an essential enzyme for the formation of the peptidoglycan wall in the bacterial cell of Mycobacterium tuberculosis. Next, I show how, through MD simulations and homology modelling, we can predict the holoprotein Sars-Covid19 Helicase structure. Lastly, I include work where I study the behaviour of known drugs while crossing a generic membrane layer, providing kinetic and structural information. Overall, this thesis demonstrates the potential of applying MD simulations to provide insights into diverse biological events. However, the application of MD simulations cannot entirely replace experimental procedures but should be a complementary method, to be applied in different biological fields, such as drug discovery.

This thesis focuses on the different liquidity issues specific to the sovereign Credit Default Swap (CDS) market. As a first step, we present an empirical study of the pricing effect of liquidity and systematic liquidity risk in the sovereign CDS spreads. We do find a large evidence that the risk premium priced above the sovereign default risk is mainly driven by both bond and CDS liquidity risk, which implies that liquidity plays an important role in CDS spread movements. Secondly, we use a factor model in order to decompose sovereign CDS spreads into default risk, liquidity and correlation components. The main objective is to measure the weight of liquidity in the CDS spreads not by using liquidity proxies such as bid-ask spreads or volumes but by calibrating the model to the data. Our analysis reveals that sovereign CDS spreads are highly driven by liquidity (55.6% of default risk and 44.32% of liquidity) and that sovereign bond spreads are less subject to liquidity frictions and therefore could represent a better proxy for sovereign default risk (73% of default risk and 26.86% of liquidity). Our empirical results advance the idea that the increase in the CDS spreads observed during the crisis period was mainly due to a surge in liquidity rather than to an increase in the default intensity. Finally, we focus on the dynamic properties of the risk neutral liquidity risk premium embedded in the term structure of sovereign CDS spreads. We show that liquidity risk has a non-trivial role and participates directly to the variation over time of the term structure of sovereign CDS spreads. Our results show that CDS buyers earned a liquidity premium only during the pre-crisis period.

Layout-induced parasitics have significant effects on the behavior of circuits in general and the performance of high-frequency analog ones in particular. To achieve parasite-inclusive performance-closure, layout-aware circuit synthesis methodologies are beginning to emerge. In layout-in-the-loop synthesis methodologies, performance analysis is based on the generation of a concrete layout for the explored circuit sizes. A parasite-inclusive circuit is extracted from the layout using a standard extractor and is analyzed using a simulator to determine whether the required constraints are met. The purpose of layout generation during the synthesis process is solely to determine the layout-induced effects in terms of device and interconnect parasites in the extracted circuit in order to perform accurate, layout-aware performance analysis. If the parasites could be estimated or determined otherwise, there would be no need for layout generation. Various approaches of estimating parasitics lack the correctness that would only come from examining the layout itself. The proposed approach tries to include the exactness of the layout to be generated without actually generating it. It relies on using pre-generated structures for the specified un-sized circuit; these structures are generated before synthesis, they contain the information that a layout would have provided to a synthesis process if it was to be generated. This information contains extraction specifics for modules, location of modules and routing characteristics. Pre-Layout Extraction: The concept of Pre-Layout Extraction shall be used to cover the extraction specific information of modules present in the circuit. It is achieved using a high-level language MSL (Module Specification Language) for the specification of parameterized, topology-specific circuit extractors. Upon compilation, the MSL program yields an executable module which generates the extracted circuit containing parasitics, passive and active devices when given specific sizes. This is done without ever generating a layout. Multi-Placement Structures: For the placement specification of the layout, Multi-Placement Structures shall be used. The proposed approach aims at retaining the benefits of both optimization-based techniques and layout templates techniques: a fast instantiation time of layout for layout-inclusive synthesis and various placement possibilities for various input sizes. ( No restriction to a single, pre-defined template ). It consists of a one-time generation of a multi-placement structure for a specific unsized circuit. The obtained structure would be used in a layout-inclusive synthesis process in the following manner: It is provided with numerical sizes from a sizing algorithm tool and returns a specific floor-plan for the circuit. For different sizes given, the aim is to have the best floor-plan returned depending on the specified sizes. Multi-Variant Routing: The remaining part of a layout description known as routing shall be handled using the proposed idea of Multi-Variant Routing. This method follows the same line of thought as its corresponding one in the placement field. It consists of a one-time generation of a Multi-Variant Routing Structure that would instantiate distinct routing schemes for distinct specified sizes and modules positions. Depending on the size of the modules in the circuit, and on their locations instantiated using the Multi-Placement Structure, the Multi-Variant Routing Structure shall be able to produce the most efficient routing scheme for the proposed circuit. Its power relies on a one-time intelligent search accomplished before synthesis, while building the structure. Depending on the locations and the sizes of the modules in the circuit, the nets in the circuit are attached to a multiple-possibility path that is controlled by the dynamic feature of changin channels and blocks’ sizes. The combination of these three described novel methods of layout approaches can be very beneficial to the synthesis of circuits and specially analog ones. It is expected to introduce a speedup factor varying from 4 to 5 with comparison to layout-inclusive synthesis approaches while having the quality of layout exploration not found in template-based approaches.