PhD Oral Exam - Philippe Archambault, Chemistry

When studying for a doctoral degree (PhD), candidates submit a thesis that provides a critical review of the current state of knowledge of the thesis subject as well as the student’s own contributions to the subject. The distinguishing criterion of doctoral graduate research is a significant and original contribution to knowledge.

Once accepted, the candidate presents the thesis orally. This oral exam is open to the public.

Abstract

Characterizing conformational variability across nucleic acid structures remains a central challenge in molecular modelling, particularly for RNA-targeting and oligonucleotide therapeutics where structure-function relationships govern recognition and efficacy. Structural descriptions are typically based on geometric criteria, while the roles of hydration, protonation, and electronic structure in defining accessible conformations remain less well established. A key unresolved question is whether conformational change is driven by intrinsic electronic effects or arises primarily from geometry-mediated responses to local environmental perturbations.

The objective of this work is to determine how local interactions govern nucleic acid conformation across multiple structural scales using electronic-structure analysis, structural data analysis, and conformational sampling. Hydration and protonation effects are examined in GAGA tetraloops and canonical base pairs to isolate geometric and electronic contributions. Backbone torsion distributions from experimental structures establish a structural baseline for canonical A-, B-, and Z-helical forms. Electron-density analysis characterizes interaction networks in GAAA, GAGA, and GCAA tetraloops, while LowModeMD generates biologically relevant states not readily accessed by conventional molecular dynamics.

Overall, nucleic acid conformational variability is governed primarily by geometric reorganization of the accessible structural landscape, with electronic structure adapting to these changes. Hydration and protonation act as modulators of conformational accessibility rather than primary drivers of electronic interaction, linking local environmental perturbations to conformational ensembles.