No és difícil trobar exemples que mostrin la inqüestionable importància de la estereoquímica en temes com la salut o l'economia: D'una banda, la quiralitat és tristament ben coneguda a causa del desastre de la Talidomida. Per altra banda, varem trobar recentment un altre exemple no menys important dins el camp de les conformacions de macromolècules: La Malaltia de Creutzfeld-Jacob. Per això, creiem que és rellevant examinar amb més detall aquells temes relacionats amb els estudis conformacionals.A la present Tesi Doctoral es proposa un procés en dues etapes per a estudiar espais conformacionals de macromolècules mitjançant Simulated Annealing (SA) i Dinàmica Molecular (DM). Ambdues metodologies són ben conegudes dins el camp de la Modelització Molecular; no obstant això, la principal contribució aportada per aquest treball és el desenvolupament d'eines metodològiques millorades -descriptors moleculars adequats, anàlisi de saturació de conformacions i grau de solapament de trajectòries- per mesurar quantitativament l'evolució i convergència dels càlculs SA i MD. / No es difícil encontrar ejemplos que muestren la incuestionable importacia de la estereoquímica en temas como la salud o la economía: Por una parte, la quiralidad es tristemente bien conocida debido al desastre de la Talidomida. Por otra parte, encontramos recientemente otro ejemplo no menos importante dentro del campo de las conformaciones de macromoléculas: La Enfermedad de Creutzfeld-Jacob. Por ello, creemos que es relevante examinar más detenidamente aquellos temas relacionados con los estudios conformacionales.En la presente Tesis Doctoral se propone un proceso en 2 etapas para estudiar espacios conformacionales de macromoléculas mediante Simulated Annealing (SA) y Dinámica Molecular (DM). Ambas metodologías son bien conocidas dentro del campo de la Modelización Molecular; sin embargo la principal contribución aportada por este trabajo es el desarrollo de herramientas metodológicas mejoradas -descriptores moleculares adecuados, análisis de saturación de conformaciones y grado de solapamiento de trayectorias- para medir cuantitativamente la evolución y convergencia de los cálculos SA y MD. / It is not difficult to find examples that show the unquestionable importance of stereochemistry in human life and economy: On the one hand, chirality is unfortunately the most well known one due to the Thalidomide Disaster. On the other hand, there is a no less important example in recent years in the field of molecular conformations: the Creutzfeldt-Jakob Disease. In this sense, we think that it is worth paying more attention to conformational studies due to their indisputable relevance.A 2-stage process for studying Conformational Spaces of large macromolecules involving Simulated Annealing (SA) Conformational Search followed by series of Molecular Dynamics (MD) calculations is proposed in this PhD Thesis. Both methodologies are well-known ones in the Molecular Modelling area of knowledge; nevertheless, the main contribution made by this research work is the development of enhanced methodological techniques -suitable molecular descriptors, saturation analysis and trajectory overlapping ratio- for monitoring quantitatively how SA and MD calculations evolve.

OmniMerge performs a systematic search to enumerate all conformations of a molecule (at a given level of torsion-angle resolution) that satisfy a set of local geometric constraints. Constraints would typically come from NMR experiments, but applications such as docking or homology modeling could also give rise to similar constraints. The molecule to be searched is partitioned into small subchains so that the set of possible conformations for the whole molecule may be constructed by merging the feasible conformations for the subchain parts. However, instead of using a binary tree for straightforward divide-and-conquer, OmniMerge defines a sub-problem for every possible subchain of the molecule. Searching every subchain provides a counter-intuitive advantage: with every possible subdivision available for merging, one may choose the most favorable merge for each subchain, particularly for the bottleneck chain(s). Improving the bottleneck step may therefore cause the whole search to be completed more quickly. Finally, to discard infeasible conformations more rapidly, OmniMerge filters the solution set of each subchain based on compatibility with the solutions sets of all overlapping subchains. These two innovations—choosing the most favorable merges and enforcing consistency between overlapping subchains—yield significant improvements in run time. By determining the extent of structural variability permitted by a set of constraints, OmniMerge offers the potential to aid error analysis and improve confidence for NMR results on peptides and moderate-sized molecules. / Singapore-MIT Alliance (SMA)

Modeling molecular structures is critical for understanding the principles that govern the behavior of molecules and for facilitating the exploration of potential pharmaceutical drugs and nanoscale designs. Biological molecules are flexible bodies that can adopt many different shapes (or conformations) until they reach a stable molecular state that is usually described by the minimum internal energy. A major challenge in modeling flexible molecules is the exponential explosion in computational complexity as the molecular size increases and many degrees of freedom are considered to represent the molecules' flexibility. This research work proposes a novel generic computational geometric approach called enhanced BioGeoFilter (g.eBGF) that geometrically interprets inter-atomic interactions to impose geometric constraints during molecular conformational search to reduce the time for identifying chemically-feasible conformations. Two new methods called Kinematics-Based Differential Evolution (kDE) and Biological Differential Evolution (BioDE) are also introduced to direct the molecular conformational search towards low energy (stable) conformations. The proposed kDE method kinematically describes a molecule's deformation mechanism while it uses differential evolution to minimize the inta-molecular energy. On the other hand, the proposed BioDE utilizes our developed g.eBGF data structure as a surrogate approximation model to reduce the number of exact evaluations and to speed the molecular conformational search. This research work will be extremely useful in enabling the modeling of flexible molecules and in facilitating the exploration of nanoscale designs through the virtual assembly of molecules. Our research work can also be used in areas such as molecular docking, protein folding, and nanoscale computer-aided design where rapid collision detection scheme for highly deformable objects is essential.