First-principles molecular structure search with a genetic algorithm

The identification of low-energy conformers for a given molecule is a fundamental problem in computational chemistry and cheminformatics. We assess here a conformer search that employs a genetic algorithm for sampling the low-energy segment of the conformation space of molecules. The algorithm is designed to work with first-principles methods, facilitated by the incorporation of local optimization and blacklisting conformers to prevent repeated evaluations of very similar solutions. The aim of the search is not only to find the global minimum, but to predict all conformers within an energy window above the global minimum. The performance of the search strategy is: (i) evaluated for a reference data set extracted from a database with amino acid dipeptide conformers obtained by an extensive combined force field and first-principles search and (ii) compared to the performance of a systematic search and a random conformer generator for the example of a drug-like ligand with 43 atoms, 8 rotatable bonds and 1 cis/trans bond

Adaptive evolution in static and dynamic environments

This thesis provides a framework for describing a canonical evolutionary system. Populations of individuals are envisaged as traversing a search space structured by genetic and developmental operators under the influence of selection. Selection acts on individuals' phenotypic expressions, guiding the population over an evaluation landscape, which describes an idealised evaluation surface over the phenotypic space. The corresponding valuation landscape describes evaluations over the genotypic space and may be transformed by within generation adaptive (learning) or maladaptive (fault induction) local search. Populations subjected to particular genetic and selection operators are claimed to evolve towards a region of the valuation landscape with a characteristic local ruggedness, as given by the runtime operator correlation coefficient. This corresponds to the view of evolution discovering an evolutionarily stable population, or quasi-species, held in a state of dynamic equilibrium by the operator set and evaluation function. This is demonstrated by genetic algorithm experiments using the NK landscapes and a novel, evolvable evaluation function, The Tower of Babel. In fluctuating environments of varying temporal ruggedness, different operator sets are correspondingly more or less adapted. Quantitative genetics analyses of populations in sinusoidally fluctuating conditions are shown to describe certain well known electronic filters. This observation suggests the notion of Evolutionary Signal Processing. Genetic algorithm experiments in which a population tracks a sinusoidally fluctuating optimum support this view. Using a self-adaptive mutation rate, it is possible to tune the evolutionary filter to the environmental frequency. For a time varying frequency, the mutation rate reacts accordingly. With local search, the valuation landscape is transformed through temporal smoothing. By coevolving modifier genes for individual learning and the rate at which the benefits may be directly transmitted to the next generation, the relative adaptedness of individual learning and cultural inheritance according to the rate of environmental change is demonstrated

Targeting the Poly (ADP-Ribose) Polymerase-1 Catalytic Pocket Using AutoGrow4, a Genetic Algorithm for De Novo Design

AutoGrow4 is a free and open-source program for de novo drug design that uses a genetic algorithm (GA) to create novel predicted small-molecule ligands for a given protein target without the constraints of a finite, pre-defined virtual library. By leveraging recent computational and cheminformatic advancements, AutoGrow4 is faster, more stable, and more modular than previous versions. Features such as docking-software compatibility, chemical filters, multithreading options, and selection methods have been expanded to support a wide range of user needs. This dissertation will cover the development and validation of AutoGrow4, as well as its application to poly (ADP-ribose) polymerase-1 (PARP-1). PARP-1 is a well-characterized DNA-damage recognition protein, and PARP-1 inhibition is an effective treatment for ovarian and breast cancers that are homologous-recombination (HR) deficient1–5. As a well-studied protein, PARP-1 is also an excellent drug target with which to validate AutoGrow4. Multiple crystallographic structures of PARP-1 bound to various PARP-1 inhibitors (PARPi) serve as positive controls for assessing the quality of AutoGrow4-generated compounds in terms of predicted binding affinity, chemical structure, and predicted protein-ligand interactions. This dissertation describes how I (1) generated novel potential PARPi with predicted binding affinities that surpass those of known PARPi; (2) validated AutoGrow4 as a tool for de novo drug design, lead optimization, and hypothesis generation, using PARP-1 as a test target; (3) contributed support to the growing notion that there is a need for HR-deficient cancer chemotherapies that do not rely on the same set of protein-ligand interactions typical of current PARPi; (4) generated novel potential PARPi that are predicted to bind to PARP-1 independent of a post-translational modification that is known to cause PARPi resistance; and (5) generated novel potential PARPi that are predicted to bind a secondary PARP-1 pocket that is distant from the primary catalytic site

How to exploit fitness landscape properties of timetabling problem: A newoperator for quantum evolutionary algorithm

© 2020 Elsevier Ltd. All rights reserved. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1016/j.eswa.2020.114211The fitness landscape of the timetabling problems is analyzed in this paper to provide some insight into theproperties of the problem. The analyses suggest that the good solutions are clustered in the search space andthere is a correlation between the fitness of a local optimum and its distance to the best solution. Inspiredby these findings, a new operator for Quantum Evolutionary Algorithms is proposed which, during the searchprocess, collects information about the fitness landscape and tried to capture the backbone structure of thelandscape. The knowledge it has collected is used to guide the search process towards a better region in thesearch space. The proposed algorithm consists of two phases. The first phase uses a tabu mechanism to collectinformation about the fitness landscape. In the second phase, the collected data are processed to guide thealgorithm towards better regions in the search space. The algorithm clusters the good solutions it has foundin its previous search process. Then when the population is converged and trapped in a local optimum, itis divided into sub-populations and each sub-population is designated to a cluster. The information in thedatabase is then used to reinitialize the q-individuals, so they represent better regions in the search space.This way the population maintains diversity and by capturing the fitness landscape structure, the algorithmis guided towards better regions in the search space. The algorithm is compared with some state-of-the-artalgorithms from PATAT competition conferences and experimental results are presented.Peer reviewe

Visualising the Search Landscape of the Triangle Program

High order mutation analysis of a software engineering benchmark, including schema and local optima networks, suggests program improvements may not be as hard to find as is often assumed. 1) Bit-wise genetic building blocks are not deceptive and can lead to all global optima. 2) There are many neutral networks, plateaux and local optima, nevertheless in most cases near the human written C source code there are hill climbing routes including neutral moves to solutions

Genetic Improvement of Software: From Program Landscapes to the Automatic Improvement of a Live System

In today’s technology driven society, software is becoming increasingly important in more areas of our lives. The domain of software extends beyond the obvious domain of computers, tablets, and mobile phones. Smart devices and the internet-of-things have inspired the integra- tion of digital and computational technology into objects that some of us would never have guessed could be possible or even necessary. Fridges and freezers connected to social media sites, a toaster activated with a mobile phone, physical buttons for shopping, and verbally asking smart speakers to order a meal to be delivered. This is the world we live in and it is an exciting time for software engineers and computer scientists. The sheer volume of code that is currently in use has long since outgrown beyond the point of any hope for proper manual maintenance. The rate of which mobile application stores such as Google’s and Apple’s have expanded is astounding. The research presented here aims to shed a light on an emerging field of research, called Genetic Improvement ( GI ) of software. It is a methodology to change program code to improve existing software. This thesis details a framework for GI that is then applied to explore fitness landscape of bug fixing Python software, reduce execution time in a C ++ program, and integrated into a live system. We show that software is generally not fragile and although fitness landscapes for GI are flat they are not impossible to search in. This conclusion applies equally to bug fixing in small programs as well as execution time improvements. The framework’s application is shown to be transportable between programming languages with minimal effort. Additionally, it can be easily integrated into a system that runs a live web service. The work within this thesis was funded by EPSRC grant EP/J017515/1 through the DAASE project