Biomolecular Binding Mechanisms at High Temporal and Structural Resolution

Biomolecular binding is pervasive in biology and governs all biological process, including DNA replication and immune recognition. Determining binding mechanisms at the atomistic-level is a significant challenge due to experimental and computational limitations. All-atom molecular dynamics simulations in conjunction with weighted ensemble (WE)-enhanced sampling has shown to be capable of generating binding trajectories in which mechanisms can be curated. In this thesis, molecular dynamics simulations in coordination with WE were implemented to determine the binding mechanism of three systems: (1) Hoechst 33258 (H33258) binding to DNA, (2) daunomycin binding to DNA, and (3) a T cell receptor (TCR) binding to a peptide/major histocompatibility complex (pMHC). We curated a binding mechanism using 2562 WE-simulated trajectories of H33258 binding to a DNA duplex. Specifically, the initial contacts between H33258 and DNA are driven electrostatically by H33258's positively charged group and the DNA's negatively charged backbone. Following the initial contacts, H33258 forms a hinge-like intermediate with one end in the minor groove of DNA. After hinge state formation, the other end of H33258 swings into the minor groove in a concerted motion and the spine of hydration along the minor groove is dehydrated. We simulated 469 trajectories of daunomycin binding to a DNA duplex. Throughout the binding process, the DNA strand underwent structural changes, including DNA base pair rise, bending, and minor groove width changes. Post-intercalation, most binding trajectories needed an additional one to five nanoseconds of rearrangement to achieve the bound configuration. 75 binding trajectories of a TCR binding to a pMHC were compiled into a binding mechanism. The initial phase of the binding process consists of contacts being formed, some forming hydrogen bonds. Hydrogen bond lifetimes vary; some persist throughout binding and others are transient. The final phase of the binding process involves water exiting the interface as final contacts form.