Determination of three-dimensional structures of proteins by simulated annealing with interproton distance restraints. Application to crambin, potato carboxypeptidase inhibitor and barley serine proteinase inhibitor 2

An automated method, based on the principle of simulated annealing,is presented for determining the three-dimensional structuresof proteins on the basis of short (<5 Å) interprotondistance data derived from nuclear Overhauser enhancement (NOE)measurements. The method makes use of Newton's equations ofmotion to increase temporarily the temperature of the systemin order to search for the global minimum region of a targetfunction comprising purely geometric restraints. These consistof interproton distances supplemented by bond lengths, bondangles, planes and soft van der Waals repulsion terms. The latterreplace the dihedral, van der Waals, electrostatic and hydrogen-bondingpotentials of the empirical energy function used in moleculardynamics simulations. The method presented involves the implementationof a number of innovations over our previous restrained moleculardynamics approach [Clore,G.M., Brünger,A.T., Karplus,M.and Gronenborn,A.M. (1986) J. Mol. Biol., 191, 523–551].These include the development of a new effective potential forthe interproton distance restraints whose functional form isdependent on the magnitude of the difference between calculatedand target values, and the design and implementation of robustand fully automatic protocol. The method is tested on threesystems: the model system crambin (46 residues) using X-raystructure derived interproton distance restraints, and potatocarboxypeptidase inhibitor (CPI; 39 residues) and barley serineproteinase inhibitor 2 (BSPI-2; 64 residues) using experimentallyderived interproton distance restraints. Calculations were carriedout starting from the extended strands which had atomic r.m.s.differences of 57, 38 and 33 Å with respect to the crystalstructures of BSPI-2, crambin and CPI respectively. Unbiasedsampling of the conformational space consistent with the restraintswas achieved by varying the random number seed used to assignthe initial velocities. This ensures that the different trajectoriesdiverge during the early stages of the simulations and onlyconverge later as more and more interproton distance restraintsare satisfied. The average backbone atomic r.m.s. differencebetween the converged structures is 2.2 ± 0.3 Åfor crambin (nine structures), 2.4 ± 0.3 Å forCPI (eight structures) and 2.5 ± 0.2 Å for BSPI-2(five structures). The backbone atomic r.m.s. difference betweenthe mean structures derived by averaging the coordinates ofthe converged structures and the corresponding X-ray structuresis 1.2 Å for crambin, 1.6 Å for CPI and 1.7 Åfor BSPI-2.     

A calculation strategy for the structure determination of symmetric dimers by 1H NMR

The structure determination of symmetric dimers by NMR is impeded by the ambiguity of inter- and intramonomer NOE crosspeaks. In this paper, a calculation strategy is presented that allows the calculation of dimer structures without resolving the ambiguity by additional experiments (like asymmetric labeling). The strategy employs a molecular dynamics-based simulated annealing approach to minimize a target function. The experimental part of the target function contains distance restraints that correctly describe the ambiguity of the NOE peaks, and a novel term that restrains the symmetry of the dimer without requiring the knowledge of the symmetry axis. The use of the method is illustrated by three examples, using experimentally obtained data and model data derived from a known structure. For the purpose of testing the method, it is assumed that every NOE crosspeak is ambiguous in all three cases. It is shown that the method is useful both in situations where the structure of a homologous protein is known and in ab initio structure determination. The method can be extended to higher order symmetric multimers.     

Flexible and Ultrasoft Inorganic 1D Semiconductor and Heterostructure Systems Based on SnIP

Low dimensionality and high flexibility are key demands for flexible electronic semiconductor devices. SnIP, the first atomic‐scale double helical semiconductor combines structural anisotropy and robustness with exceptional electronic properties. The benefit of the double helix, combined with a diverse structure on the nanoscale, ranging from strong covalent bonding to weak van der Waals interactions, and the large structure and property anisotropy offer substantial potential for applications in energy conversion and water splitting. It represents the next logical step in downscaling the inorganic semiconductors from classical 3D systems, via 2D semiconductors like MXenes or transition metal dichalcogenides, to the first downsizeable, polymer‐like atomic‐scale 1D semiconductor SnIP. SnIP shows intriguing mechanical properties featuring a bulk modulus three times lower than any IV, III‐V, or II‐VI semiconductor. In situ bending tests substantiate that pure SnIP fibers can be bent without an effect on their bonding properties. Organic and inorganic hybrids are prepared illustrating that SnIP is a candidate to fabricate flexible 1D composites for energy conversion and water splitting applications. SnIP@C₃N₄ hybrid forms an unusual soft material core–shell topology with graphenic carbon nitride wrapping around SnIP. A 1D van der Waals heterostructure is formed capable of performing effective water splitting.     

Heteronuclear relaxation study of the PH domain of beta-spectrin: restriction of loop motions upon binding inositol trisphosphate

The structural dynamics of protein ligand binding sites is one factor determining the specificity towards related ligands. In this context, the spectrin PH domain, which binds to a number of phosphatidylinositol lipid head groups, was investigated with respect to the dynamics of the binding loops. The latter were found to be of intermediate flexibility on a picosecond to nanosecond time-scale in the free protein and become more rigid upon ligand binding. Significant 15N and proton chemical shift changes occur in the binding loops. The internal correlation time, determined from 15N heteronuclear relaxation data using the standard model-free approach, decreases upon ligand binding. For several residues a concomitant rise in the generalized order parameter is observed. This is interpreted as a dampening effect of the ligand on a slow loop motion, while a fast component is not affected. Molecular dynamics simulations were performed to further investigate this situation. In fact, two time-scales of loop motions in the free state are observed in a 9 ns molecular dynamics trajectory. Agreement with generalized order parameters obtained from the experiment improves when a subtrajectory is analyzed that excludes rare dihedral transitions.     

Structure calculation from NMR data

NMR calculation methods have kept pace with the rapid extension of NMR experiments to larger molecules. By including additional data and effects of local dynamics in the refinement, we can obtain a more complete picture of the molecule in solution. The structure determination process is being aided by new methods to solve some aspects of spectral assignment during the structure calculation.