The science and technology of catalysis is more important today than at any other time in our history due to the grand energy and environment challenges we are facing. With the explosively growth of computation power nowadays, computer simulation can play an increasingly important role in the design of new catalysts, avoiding the costly trail-and-error attempts and facilitating the development cycle. The goal to inverse design of new materials with desired catalytic property was once far off, but now achievable. The major focus of this dissertation is to find the general rules that govern the catalytic performance of a nanoparticle as the function of its structure. Three types of multi-metallic nanoparticles have been investigated in this dissertation, core-shell, random alloy and alloy-core@shell. Significant structural rearrangement was found on Au@Pt and Pd@Pt nanoparticle, which is responsible for a dramatic improvement in catalytic performance. Nonlin- ear binding trends were found and modeled for random alloy nanoparticles, providing a prescription for tuning catalytic activity through alloying. Studies of ORR on Pd/Au random alloy NP and hydrogenation reaction on Rh/Ag random alloy NP revealed that binding on individual ensemble should be in- vestigated when large disparity of adsorbate affinity is presented between two alloying elements. In the alloy-core@shell system, I demostrated a general linear correlations between the adsorbate binding energy to the shell of an alloy-core@shell nanoparticle and the composition of the core. This relation- ship allows for interpolation of the properties of single-core@shell particles and an approach for tuning the catalytic activity of the particle. A series of promising catalysts were then predicted for ORR, HER and CO oxidation. As a first attempt to bridge the material gap, bimetallic nano clus- ter supported on CeO₂(111) was investigated for CO oxidation. A strong support-metal interaction induces a preferential segregation of the more reac- tive element to the NC-CeO₂ perimeter, generating an interface with the Au component. (Au-Cu)/CeO₂ was found to be optimal for catalyzing CO oxida- tion via a bifunctional mechanism. O₂ preferentially binds to the Cu-rich sites whereas CO binds to the Au-rich sites. A method called distributed replica dynamics (DRD) is proposed at last to utilize enormous distributed computing resources for molecular dynamics simulations of rare-event in chemical reac- tions. High efficiency can be achieved with an appropriate choice of N [subscript rep] and t [subscript rep] for long-time MD simulation. / text

Cyclophilin A (CypA) is the well-studied member of a group of ubiquitous and evolutionarily conserved families of enzymes called peptidyl–prolyl isomerases (PPIases). These enzymes catalyze the cis-trans isomerization of peptidyl-prolyl bond in many proteins. The distinctive functional path triggered by each isomeric state of peptidyl-prolyl bond renders PPIase-catalyzed isomerization a molecular switching mechanism to be used on physiological demand. PPIase activity has been implicated in protein folding, signal transduction, and ion channel gating as well as pathological condition such as cancer, Alzheimer’s, and microbial infections. The more than five order of magnitude speed-up in the rate of peptidyl–prolyl cis–trans isomerization by CypA has been the target of intense research. Normal and accelerated molecular dynamic simulations were carried out to understand the catalytic mechanism of CypA in atomistic details. The results reaffirm transition state stabilization as the main factor in the astonishing enhancement in isomerization rate by enzyme. The ensuing intramolecular polarization, as a result of the loss of pseudo double bond character of the peptide bond at the transition state, was shown to contribute only about −1.0 kcal/mol to stabilizing the transition state. This relatively small contribution demonstrates that routinely used fixed charge classical force fields can reasonably describe these types of biological systems. The computational studies also revealed that the undemanding exchange of the free substrate between β- and α-helical regions is lost in the active site of the enzyme, where it is mainly in the β-region. The resultant relative change in conformational entropy favorably contributes to the free energy of stabilizing the transition state by CypA. The isomerization kinetics is strongly coupled to the enzyme motions while the chemical step and enzyme–substrate dynamics are in turn buckled to solvent fluctuations. The chemical step in the active site of the enzyme is therefore not separated from the fluctuations in the solvent. Of special interest is the nature of catalysis in a more realistic crowded environment, for example, the cell. Enzyme motions in such complicated medium are subjected to different viscosities and hydrodynamic properties, which could have implications for allosteric regulation and function.

Pin1 is an enzyme central to cell signaling pathways because it catalyzes the cis–trans isomerization of the peptide ω-bond in phosphorylated serine/threonine-proline motifs in many proteins. This regulatory function makes Pin1 a drug target in the treatment of various diseases. The effects of phosphorylation on Pin1 substrates and the basis for Pin1 recognition are not well understood. The conformational consequences of phosphorylation on Pin1 substrate analogues and the mechanism of recognition by the catalytic domain of Pin1 were determined using molecular dynamics simulations. Phosphorylation perturbs the backbone conformational space of Pin1 substrate analogues. It is also shown that Pin1 recognizes specific conformations of its substrate by conformational selection. Dynamical correlated motions in the free Pin1 enzyme are present in the enzyme of the enzyme–substrate complex when the substrate is in the transition state configuration. This suggests that these motions play a significant role during catalysis. These results provide a detailed mechanistic understanding of Pin1 substrate recognition that can be exploited for drug design purposes and further our understanding of the subtleties of post-translational phosphorylation and cis–trans isomerization. Results from accelerated molecular dynamics simulations indicate that catalysis occurs along a restricted path of the backbone configuration of the substrate, selecting specific subpopulations of the conformational space of the substrate in the active site of Pin1. The simulations show that the enzyme–substrate interactions are coupled to the state of the prolyl peptide bond during catalysis. The transition-state configuration of the substrate binds better than the cis and trans states to the catalytic domain of Pin1. This suggests that Pin1 catalyzes its substrate by noncovalently stabilizing the transition state. These results suggest an atomistic detail understanding of the catalytic mechanism of Pin1 that is necessary for the design of novel inhibitors and the treatment of several diseases. Additionally, a set of constant force biased molecular dynamics simulations are presented to explore the kinetic properties of a Pin1 substrate and its unphosphorylated analogue. The simulations indicate that the phosphorylated Pin1 substrate isomerizes slower than the unphosphorylated analogue. This is due to the lower diffusion constant for the phosphorylated Pin1 substrate.

Dans ce travail, nous avons étudié l’adsorption dissociative de l’hydrogène sur Pd(111) ainsi que la diffusion d’un atome de l’hydrogène sur ce même surface. A l’aide de la théorie de la fonctionnelle de la densité, nous avons mené une étude systématique de l’effet du recouvrement en surface sur l’énergétique de la dissociation de H2 sur une surface de Pd(111) couverte par des atomes de l’hydrogène. Un résultat surprenant que nous avons trouvé est que les atomes adsorbés ont non seulement un effet de poison mais peuvent aussi promouvoir la dissociation de H2 s’ils sont adsorbés sur des sites loin de la molécule d’hydrogène qui dissocie. En ce qui concerne la diffusion d’un atome d’ hydrogène sur Pd(111), nous avons déterminé le coefficient de diffusion par des simulations de dynamique moléculaire en utilisant la formule d’Einstein à différente température de la surface, Ts=500K, 300K and 250K. Une méthode de la dynamique moléculaire accélérée a été développée afin d’étudier la diffusion à bases températures. Dans notre approche, l’accélération se fait moyennant l’augmentation de l’énergie cinétique de l’atome qui diffuse suivant une distribution Maxwell-Boltzmann qui correspond à une température plus élevée et la correction de l’échelle de temps d’une façon consistante. Pour tester la validité de notre approche, nous avons effectué des simulations pour la diffusion d’un atome d’hydrogène sur Pd(111) à Ts=300K and Ts=100K. Les résultats obtenus par la méthode accélérée est en bon accord avec ceux de la simulation standard. Par la méthode accélérée, l’échelle de temps peut être étendu à l’ordre de micro-secondes. / In this thesis, we studied dissociative adsorption of hydrogen on Pd(111) with particular attention paid to the surface coverage effect and the diffusion of a hydrogen adatom on Pd(111). With the help of DFT calculations, we carried out a systematic investigation of the effect of H-adatoms on the dissociation energetics of H2 on H-covered Pd(111) surfaces at various coverages. A quite surprising finding is that the H-adatoms do not only have a poisoning effect but can also promote H2 dissociation when they are adsorbed on sites which are sufficiently far from the dissociating H2 molecule. The macroscopic diffusion coefficient of an H-adatom on Pd(111) is determined from molecular dynamics simulations with the help of Einstein formula for different surface temperatures, i.e., Ts=500K, 300K and 250K. An accelerated molecular dynamics method was developed in order to study the diffusion at low surface temperatures. In our approach, the acceleration is achieved by increasing the kinetic energy of the diffusing atom according to the Maxwell-Boltzmann distribution at a higher temperature and correcting the time scale in a consistent way. For testing the validity of our method, we performed simulations for the diffusion of H adatom on Pd(111) surface at T=300K and T=100K. The diffusion coefficient obtained from the accelerated MD method is in agreement with that obtained from the direct MD and TST methods. And the physical time scale can be extended to the order of microseconds.

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