"Lipid recognition propensities of amino acids in membrane proteins from atomic resolution data"
Protein-lipid interactions play essential roles in the conformational stability and biological functions of membrane proteins. However, few of the previous computational studies have taken into account the atomic details of protein-lipid interactions explicitly.
To gain an insight into the molecular mechanisms of the recognition of lipid molecules by membrane proteins, we investigated amino acid propensities in membrane proteins for interacting with the head and tail groups of lipid molecules. We observed a common pattern of lipid tail-amino acid interactions in two different data sources, crystal structures and molecular dynamics simulations. These interactions are largely explained by general lipophilicity, whereas the preferences for lipid head groups vary among individual proteins. We also found that membrane and water-soluble proteins utilize essentially an identical set of amino acids for interacting with lipid head and tail groups.
We showed that the lipophilicity of amino acid residues determines the amino acid preferences for lipid tail groups in both membrane and water-soluble proteins, suggesting that tightly-bound lipid molecules and lipids in the annular shell interact with membrane proteins in a similar manner. In contrast, interactions between lipid head groups and amino acids showed a more variable pattern, apparently constrained by each protein’s specific molecular function.
"Structural Diversity and Changes in Conformational Equilibria of Biantennary Complex-Type N-Glycans in Water Revealed by Replica-Exchange Molecular Dynamics Simulation"
Structural diversity of N-glycans is essential for specific binding to their receptor proteins. To gain insights into structural and dynamic aspects in atomic detail not normally accessible by experiment, we here perform extensive molecular-dynamics simulations of N-glycans in solution using the replica-exchange method. The simulations show that five distinct conformers exist in solution for the N-glycans with and without bisecting GlcNAc. Importantly, the population sizes of three of the conformers are drastically reduced upon the introduction of bisecting GlcNAc. This is caused by a local hydrogen-bond rearrangement proximal to the bisecting GlcNAc. These simulations show that an N-glycan modification like the bisecting GlcNAc selects a certain "key" (or group of "keys") within the framework of the "bunch of keys" mechanism. Hence, the range of specific glycan-protein interactions and affinity changes need to be understood in terms of the structural diversity of glycans and the alteration of conformational equilibria by core modification.
"Functionality Mapping on Internal Surfaces of Multidrug Transporter AcrB Based on Molecular Theory of Solvation: Implications for Drug Efflux Pathway"
AcrB is a membrane protein acting as a multidrug efflux transporter. Although the recently-solved X-ray crystal structures of AcrB provided a rough sketch for the drug efflux mechanism, the pathway has not been completely elucidated in atomic resolution. In this study, a ligand-mapping method based on the molecular theory of solvation, which has been recently developed by ourselves, is applied to AcrB in order to identify the drug efflux pathway. As an effective strategy, a fragment-based approach is adopted to map chemical functionality on the internal surfaces. As a result, a few “multifunctional” ligand-binding sites, which recognize various types of functional groups, are detected inside the porter domain. A spatial link between the multi-functional sites indicates a probable multidrug efflux pathway. The chemical and physical driving forces to ingest and transport drugs are also discussed.
"Geometrically Associative Yet Electronically Dissociative Character in the Transition State of Enzymatic Reversible Phosphorylation"
Reversible phosphorylation of proteins is a post-translational modification that regulates diverse biological processes. The molecular mechanism underlying phosphoryl transfer catalyzed by enzymes remains a subject of active debate. In particular, the nature of transition state (TS), whether it has an associative or dissociative character, has been one of the most controversial issues. Structural evidence supports an associative TS, whereas physical organic studies point to a dissociative character. Here we perform hybrid quantum mechanics/molecular mechanics simulations for the reversible phosphorylation of phosphoserine phosphatase (PSP) to study the nature of the TS. Both phosphorylation and dephosphorylation reactions are investigated based on the two-dimensional energy surfaces along phosphoryl and proton transfer coordinates. The structures of the active site at TS in both reactions reveal compact geometries, consistent with crystal structures of PSP with phosphate analogues. On the other hand, the electron density of the phosphoryl group in both TS structures slightly decreases compared with that in the reactant states. These findings suggest that the TS of PSP has a geometrically associative yet electronically dissociative character and strongly depends on proton transfer being coupled with phosphoryl transfer. Structure and literature database searches on phosphotransferases suggest that such a hybrid TS is consistent with many structures and physical organic studies and likely holds for most enzymes catalyzing phosphoryl transfer.