Membrane proteins that function as transporters or receptors must communicate with both sides of the lipid bilayer in which they sit. This long distance communication enables transporters to move protons or other ions and small molecules across the bilayer and receptors to transmit an external signal to the cell. Hydrogen bonds, hydrogen-bond networks, and lipid−protein interactions are essential for the motions and functioning of the membrane protein and, consequently, of outmost interest to structural biology and numerical simulations. We present here Bridge, an algorithm tailored for efficient analyses of hydrogen-bond networks in membrane transporter and receptor proteins. For channelrhodopsin, a membrane protein whose functioning involves proton-transfer reactions, Bridge identifies extensive networks of protein−water hydrogen bonds and an unanticipated network that can bridge transiently two proton donors across a distance of ∼20 Å. Graphs of the protein hydrogen bonds reveal rapid propagation of structural changes within hydrogen-bond networks of mutant transporters and identify protein groups potentially important for the proton transfer activity. The algorithm is made available as a plugin for PyMol.

Photosystem II uses the energy of absorbed light to split water molecules, generating molecular oxygen, electrons, and protons. The four protons generated during each reaction cycle are released to the lumen via mechanisms that are poorly understood. Given the complexity of photosystem II, which consists of multiple protein subunits and cofactor molecules and hosts numerous waters, a fundamental issue is finding transient networks of hydrogen bonds that bridge potential proton donor and acceptor groups. Here, we address this issue by performing all-atom molecular dynamics simulations of wild-type and mutant photosystem II monomers, which we analyze using a new protocol designed to facilitate efficient analysis of hydrogen-bond networks. Our computations reveal that local protein/water hydrogen-bond networks can assemble transiently in photosystem II such that the reaction center connects to the lumen. The dynamics of the hydrogen-bond networks couple to the protonation state of specific carboxylate groups and are altered in a mutant with defective proton transfer. Simulations on photosystem II without its extrinsic PsbO subunit provide a molecular interpretation of the elusive functional role of this subunit.

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Proton transfer over distances longer than that of a hydrogen bond often requires water molecules and protein motions. Following transfer of the proton from the donor to the acceptor, the change in the charge distribution may alter the dynamics of protein and water. To begin to understand how protonation dynamics couple to protein and water dynamics, here we explore how changes in the protonation state affect water and protein dynamics in the AHA2 proton pump. We find that the protonation state of the proton donor and acceptor groups largely affects the dynamics of internal waters and of specific hydrogen bonds, and the orientation of transmembrane helical segments that couple remote regions of the protein. The primary proton donor/acceptor group D684, can interact with water molecules from the cytoplasmic bulk and/or other protein groups.

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