Nikolay A. Krylov

PLATINUM: a web tool for analysis of hydrophobic/hydrophilic organization of biomolecular complexes

UNLABELLED The PLATINUM (Protein-Ligand ATtractions Investigation NUMerically) web service is designed for analysis and visualization of hydrophobic/hydrophilic properties of biomolecules supplied as 3D-structures. Furthermore, PLATINUM provides a number of tools for quantitative characterization of the hydrophobic/hydrophilic match in biomolecular complexes e.g. in docking poses. These complement standard scoring functions. The calculations are based on the concept of empirical Molecular Hydrophobicity Potential (MHP). AVAILABILITY The PLATINUM web tool as well as detailed documentation and tutorial are available free of charge for academic users at http://model.nmr.ru/platinum/. PLATINUM requires Java 5 or higher and Adobe Flash Player 9. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.

Kalium: a database of potassium channel toxins from scorpion venom

Kalium (http://kaliumdb.org/) is a manually curated database that accumulates data on potassium channel toxins purified from scorpion venom (KTx). This database is an open-access resource, and provides easy access to pages of other databases of interest, such as UniProt, PDB, NCBI Taxonomy Browser, and PubMed. General achievements of Kalium are a strict and easy regulation of KTx classification based on the unified nomenclature supported by researchers in the field, removal of peptides with partial sequence and entries supported by transcriptomic information only, classification of β-family toxins, and addition of a novel λ-family. Molecules presented in the database can be processed by the Clustal Omega server using a one-click option. Molecular masses of mature peptides are calculated and available activity data are compiled for all KTx. We believe that Kalium is not only of high interest to professional toxinologists, but also of general utility to the scientific community. Database URL: http://kaliumdb.org/

Atomic-scale lateral heterogeneity and dynamics of two-component lipid bilayers composed of saturated and unsaturated phosphatidylcholines

Studies of lateral heterogeneity in cell membranes are important since they help to understand the physical origin of lipid domains and rafts. The simplest membrane mimics are hydrated bilayers composed of saturated and unsaturated lipids. While their atomic structural details resist easy experimental characterization, important insight can be gained via computer modeling. We present the results of all-atom molecular dynamics simulations for a series of fluid dioleoylphosphatidylcholine (DOPC) and dipalmitoylphosphatidylcholine (DPPC) bilayers. Lateral arrangement of lipids in these systems is not random and reveals small geometrical and hydrophobic clusters on the surface. Being “sharp” inside the bilayer, lateral heterogeneity is very “fuzzy” on the surface. This picture is highly dynamic – lifetimes of clusters are ∼1 ns. In the binary system, DPPC acts as an “order-preferring” agent, which efficiently modulates behavior of DOPC. Bilayer properties are tuned in a wide range by the chemical nature and relative content of lipids. The impact that the micro-heterogeneity may have on formation of lateral domains in response to external signals is discussed. Understanding of such effects creates a basis for rational design of artificial membranes with predefined properties.

Liquid but Durable: Molecular Dynamics Simulations Explain the Unique Properties of Archaeal-Like Membranes

Archaeal plasma membranes appear to be extremely durable and almost impermeable to water and ions, in contrast to the membranes of Bacteria and Eucaryota. Additionally, they remain liquid within a temperature range of 0–100°C. These are the properties that have most likely determined the evolutionary fate of Archaea, and it may be possible for bionanotechnology to adopt these from nature. In this work, we use molecular dynamics simulations to assess at the atomistic level the structure and dynamics of a series of model archaeal membranes with lipids that have tetraether chemical nature and “branched” hydrophobic tails. We conclude that the branched structure defines dense packing and low water permeability of archaeal-like membranes, while at the same time ensuring a liquid-crystalline state, which is vital for living cells. This makes tetraether lipid systems promising in bionanotechnology and material science, namely for design of new and unique membrane nanosystems.

Dynamic clustering of lipids in hydrated two-component membranes: results of computer modeling and putative biological impact

Delineation and analysis of lateral clustering of lipids in model bilayers is an important step toward understanding of the physical processes underlying formation of lipid domains and rafts in cell membranes. Computer modeling methods represent a powerful tool to address the problem since they can detect clusters of only few lipid molecules – this issue still resists easy characterization with modern experimental techniques. In this work, we propose a computational method to detect and analyze parts of membrane with different packing densities and hydrogen bonding patterns. A series of one- and two-component fluid systems containing lipids with the same polar heads and different acyl chains, dioleoylphosphatidylcholine (18:1) and dipalmitoylphosphatidylcholine (16:0), or with same acyl chains and different polar heads, dioleoylphosphatidylserine (18:1) and dioleoylphosphatidylcholine (18:1), were studied via molecular dynamics simulations. Four criteria of clustering were considered. It was shown that the water–lipid interface of biomembranes represents a highly dynamic and “mosaic” picture, whose parameters depend on the bilayer composition. Some systems (e.g. with 20–30% of the anionic lipid) demonstrate unusual clustering properties and demand further investigation at molecular level. Lateral microheterogeneities in fluid lipid bilayers seem to be among the most important factors determining the nature of the membrane–water interface in a cell.

Temperature-sensitive gating of TRPV1 channel as probed by atomistic simulations of its trans- and juxtamembrane domains

Heat-activated transient receptor potential channel TRPV1 is one of the most studied eukaryotic proteins involved in temperature sensation. Upon heating, it exhibits rapid reversible pore gating, which depolarizes neurons and generates action potentials. Underlying molecular details of such effects in the pore region of TRPV1 is of a crucial importance to control temperature responses of the organism. Despite the spatial structure of the channel in both open (O) and closed (C) states is known, microscopic nature of channel gating and mechanism of thermal sensitivity are still poorly understood. In this work, we used unrestrained atomistic molecular dynamics simulations of TRPV1 (without N- and C-terminal cytoplasmic domains) embedded into explicit lipid bilayer in its O- and C-states. We found that the pore domain with its neighboring loops undergoes large temperature-dependent conformational transitions in an asymmetric way, when fragments of only one monomer move with large amplitude, freeing the pore upon heating. Such an asymmetrical gating looks rather biologically relevant because it is faster and more reliable than traditionally proposed “iris-like” symmetric scheme of channel opening. Analysis of structural, dynamic, and hydrophobic organization of the pore domain revealed entropy growth upon TRPV1 gating, which is in line with current concepts of thermal sensitivity.

Lateral clustering of lipids in hydrated bilayers composed of dioleoylphosphatidylcholine and dipalmitoylphosphatidylcholine

Investigation of lateral heterogeneities (clusters) in cell membranes is an important step toward understanding the physical processes that lead to the formation of lipid domains and rafts. Computer modeling methods represent a powerful tool to solve the problem, since they can detect clusters containing only a few lipid molecules—the situation that still resists characterization with modern experimental techniques. Parameters of clustering depend on lipid composition of a membrane. In this work, we propose a computational method to detect and analyze parts of membrane with different packing densities. Series of one- and two-component fluid systems containing lipids with the same polar heads and different acyl chains, dioleoylphosphatidylcholine (18 : 1) and dipalmitoylphosphatidylcholine (16 : 0), were chosen as the objects under study. The developed algorithm is based on molecular dynamics simulation of hydrated lipid bilayers in all-atom mode. The method is universal and could be applied to any other membrane system with arbitrary lipid composition. Here, we demonstrated that the studied lipid bilayers reveal small lateral dynamic clusters composed of just several (most often, three) lipid molecules. This seems to be one of the most important reasons determining the “mosaic” nature of the membrane-water interface.

Complementarity of Hydrophobic/Hydrophilic Properties In Protein—Ligand Complexes: A New Tool to Improve Docking Results

Computational techniques designed to predict the spatial structure of ligand-receptor complexes (molecular docking) are widely used in investigations of molecular details of protein functioning and in drug design. Here, a brief review of docking methods is given and recent advances in improvement of their accuracy and efficiency are discussed. Two acute problems of standard docking algorithms are considered: proper ranking of putative docking solutions and simulation of receptor flexibility. The recent trends to overcome these problems are demon- strated with the results obtained in our Laboratory. Particular attention is paid to protein-ligand hydrophobic and stacking interactions, which are not always adequately represented in scoring criteria of docking applications.