Molecular Mechanics Energy Calculations Research Articles

A rotamer library to enable modeling and design of peptoid foldamers.

Peptoids are a family of synthetic oligomers composed of N-substituted glycine units. Along with other “foldamer” systems, peptoid oligomer sequences can be predictably designed to form a variety of stable secondary structures. It is not yet evident if foldamer design can be extended to reliably create tertiary structure features that mimic more complex biomolecular folds and functions. Computational modeling and prediction of peptoid conformations will likely play a critical role in enabling complex biomimetic designs. We introduce a computational approach to provide accurate conformational and energetic parameters for peptoid side chains needed for successful modeling and design. We find that peptoids can be described by a “rotamer” treatment, similar to that established for proteins, in which the peptoid side chains display rotational isomerism to populate discrete regions of the conformational landscape. Because of the insufficient number of solved peptoid structures, we have calculated the relative energies of side-chain conformational states to provide a backbone-dependent (BBD) rotamer library for a set of 54 different peptoid side chains. We evaluated two rotamer library development methods that employ quantum mechanics (QM) and/or molecular mechanics (MM) energy calculations to identify side-chain rotamers. We show by comparison to experimental peptoid structures that both methods provide an accurate prediction of peptoid side chain placements in folded peptoid oligomers and at protein interfaces. We have incorporated our peptoid rotamer libraries into ROSETTA, a molecular design package previously validated in the context of protein design and structure prediction.

ChemInform Abstract: Synthesis of Proline-Valine Pseudodipeptide Enol Lactones, Serine Protease Inhibitors.

Pseudodipeptides of proline-valine that incorporate protio or halo enol lactone moieties have been synthesized from common acetylenic acid precursors; in each case, two diasteromers were prepared in enantiomerically pure form. The preparation began with isomeric propargylic alcohols derived from L-prolinal, which are further elaborated into the methyleneoxy valine pseudodipeptide analogues via an oxalactam intermediate. The pseudodipeptide acetylenic acids could by cyclized to the protio enol lactones by mercuric salts and could be elaborated to tetrapeptide analogues either before or after cyclization. The relative stability of the two diastereomeric enol lactone systems toward intramolecular acyl transfer could be rationalized by molecular mechanics energy calculations on ground-state and tetrahedral intermediates believed to be involved in the reaction. While the halo enol lactones derived from the pseudotetrapeptides proved to be very unstable, they could be prepared from the n-butyl carbamate derivatives of the dipeptide

A Finite Element Framework for Studying the Mechanical Response of Macromolecules: Application to the Gating of the Mechanosensitive Channel MscL

The gating pathways of mechanosensitive channels of large conductance (MscL) in two bacteria ( Mycobacterium tuberculosis and Escherichia coli) are studied using the finite element method. The phenomenological model treats transmembrane helices as elastic rods and the lipid membrane as an elastic sheet of finite thickness; the model is inspired by the crystal structure of MscL. The interactions between various continuum components are derived from molecular-mechanics energy calculations using the CHARMM all-atom force field. Both bacterial MscLs open fully upon in-plane tension in the membrane and the variation of pore diameter with membrane tension is found to be essentially linear. The estimated gating tension is close to the experimental value. The structural variations along the gating pathway are consistent with previous analyses based on structural models with experimental constraints and biased atomistic molecular-dynamics simulations. Upon membrane bending, neither MscL opens substantially, although there is notable and nonmonotonic variation in the pore radius. This emphasizes that the gating behavior of MscL depends critically on the form of the mechanical perturbation and reinforces the idea that the crucial gating parameter is lateral tension in the membrane rather than the curvature of the membrane. Compared to popular all-atom-based techniques such as targeted or steered molecular-dynamics simulations, the finite element method-based continuum-mechanics framework offers a unique alternative to bridge detailed intermolecular interactions and biological processes occurring at large spatial scales and long timescales. It is envisioned that such a hierarchical multiscale framework will find great value in the study of a variety of biological processes involving complex mechanical deformations such as muscle contraction and mechanotransduction.

Differential modes of agonist binding to 5-hydroxytryptamine(2A) serotonin receptors revealed by mutation and molecular modeling of conserved residues in transmembrane region 5.

Site-directed mutagenesis and molecular modeling were used to investigate the molecular interactions involved in ligand binding to, and activation of, the rat 5-hydroxytryptamine(2A) (5-HT(2A)) serotonin (5-HT) receptor. Based on previous modeling studies utilizing molecular mechanics energy calculations and molecular dynamics simulations, four sites (S239[5.43], F240[5.44], F243[5.47], and F244[5.48]) in transmembrane region V were selected, each predicted to contribute to agonist and/or antagonist binding. The F243A mutation increased the affinity of (+/-)4-iodo-2, 5-dimethoxyphenylisopropylamine, decreased the binding of alpha-methyl-5HT, N-omega-methyl-5HT, ketanserin, ritanserin, and spiperone and had no effect on the binding of 5-HT and 5-methyl-N, N-dimethyltryptamine. The F240A mutant had no effect on the binding of any of the ligands tested, whereas F244A caused an agonist-specific decrease in binding affinity (3- to 10-fold). S239A caused a 6- to 13-fold decrease in tryptamine-binding affinity and a 5-fold increase in affinity of 4-iodo-2, 5-dimethoxyphenylisopropylamine. A subset of the agonists used in binding studies were used to determine the efficacies and potencies of these mutants to activate phosphoinositide hydrolysis. The F243A and F244A mutations reduced agonist stimulated phosphoinositide hydrolysis, whereas the S239A and F240A mutations had no effect. There was little correlation between agonist binding and second messenger production. Furthermore, molecular dynamics simulations, considering these data, produced ligand-bound structures utilizing substantially different bonding interactions even among structurally similar ligands (differing by as little as one methyl group). Taken together, these results suggest that relatively minor changes in either receptor or ligand structure can produce drastic and unpredictable changes in both binding interactions and 5-HT(2A) receptor activation. Thus, our finding may have major implications for the future and feasibility of receptor structure-based drug design.

Analogous salicylic acid affinity regions in serum albumin and soybean β‐Conglycinin

AbstractThe known structures of human serum albumin and its binding sites for salicylic acid (SA) were used as a model for examining the amino acid sequence of soybean β‐conglycinin to determine whether a plant protein might share structural similarities with albumin relative to the binding of SA, Molecular mechanics energy calculations for computed nonionized and ionized interactions in vacuo identified the two major SA affinity regions in human serum albumin and a single analogous region in the α‐subunit of soybean β‐conglycinin. SA interactions with 21‐residue segments from both proteins suggest redundant binding sites with multiple degrees of affinity. Highaffinity segments incorporate hydrophobic amino acids with combinations or multiple residues of histidine, tryptophan, lysine, or arginine in keeping with a preference of SA for homopolymers of these acids over other homopolypeptides. Residue spacing also seems important. High affinity is associated with but not imparted by genetic similarity. Profiles from β‐sheet conformations simplify identification of analogous segments.

Molecular Mechanics Energy Calculations for the Double-Stranded Helices of Isotactic Poly(methyl methacrylate) Large Oligomers

For isotactic poly(methyl methacrylate), molecular mechanics energy calculations were carried out on several double-stranded helix oligomer models for analyzing the energetical stability of the polymer double-stranded helix determined by X-ray analysis. The calculation results indicate that the double-stranded-helix structures can exist as stable double-stranded helices by the favorable intertwined interactions of the van der Waals interactions for the large oligomers (n≥10; n is the number of monomers in the oligomer). Moreover, the calculated double-stranded helix structure by the energy minimization method is in good agreement with the observed structure by X-ray analysis.

X-Ray and Energy Calculation Studies on the Packing-Mode of Double-Stranded Helices of Isotactic Poly(methyl methacrylate)

For isotactic poly(methyl methacrylate) (it-PMMA), structural reasons on the rather complicated crystal structure with the space group Fdd2 determined by X-ray analysis were investigated. The X-ray diffraction intensity distribution of the first layer line was found to reflect the locations of the (10/1) double-stranded helices along the c-axis. And the energy calculation indicated that the packing-mode of double-stranded helices accompanying the space group Fdd2 is ∼2.0–2.5 kcal mol−1 monomer−1 more stable than those with Pnn2, Pba2, and P21/a as calculated by molecular mechanics energy calculations. For it-PMMA, the present X-ray study and crystal energy calculations support the rather complicated crystal structure.

Synthesis of Sugar-Derived Nitrogen Heterocycles

The synthesis of nitrogen heterocycles through condensation of stereoisomeric butane-1,2,3,4-tetramines with aldehydes, and their structure elucidation through spectroscopic methods are described. Significant differences in the products from each of the amines were observed due to differences in the relative stereochemistry of the amines. Molecular mechanics energy calculations when carried out on all possible products from the condensation of both the threo and erythro tetramines with acetaldehyde revealed minimum energy structures that were consistent with those found experimentally. The products were therefore probably the result of thermodynamic control.

Conformationally constrained o-tolylpiperazine camphorsulfonamide oxytocin antagonists. Structural modifications that provide high receptor affinity and suggest a bioactive conformation.

A series of new o-tolylpiperazine camphorsulfonamide OT antagonists is described. Analogs containing conformationally constrained 1-acylamino-2-propyl substituents at the camphor C2 endo position exhibit high affinity for OT and AVP-V 1a receptors or high affinity and selectivity for OT receptors, depending on functionalities present in the acyl group. Determination of the preferred conformation of potency-enhancing 1-acylamino-2-propyl substituents using molecular mechanics energy calculations and X-ray crystallography, along with topological similarities to a conformationally constrained cyclic hexapeptide OT antagonist, suggests a receptor-bound conformation for this series of non-peptide OT antagonists.

Molecular dynamics of serotonin and ritanserin interacting with the 5-HT 2 receptor

A three-dimensional model of the serotonin (5-hydroxytrytamine; 5-HT) 5-HT 2 receptor was constructed from the amino acid sequence by molecular graphics techniques, molecular mechanics energy calculations and molecular dynamics simulations. The receptor model has 7 α helical segments which form a membrane-spanning duct with a putative ligand binding site. Most of the synaptic domains and the ligand binding site were surrounded by negative electrostatic potentials, suggesting that positively charged ligands are attracted to the receptor by electrostatic forces. The cytoplasmic domains, except the C-terminal tail, had mainly positive electrostatic potentials. The molecular dynamics of the receptor — ligand complex was examined in 100 ps simulations with 5-HT or ritanserin at a postulated binding site. During the simulations the helices moved from an initial circular arrangement into a more oval arrangement, and became slightly tilted relative to each other. The protonated ligands neutralized the negative electrostatic potentials around Asp 120 and Asp 155 in the central core of the receptor. 5-HT had only weak interactions with Asp 155 but strong interactions with Asp 120 during the simulations, with the amino group of 5-HT tightly bound to the carboxylic side chain of Asp 120. Ritanserin showed similarly strong interactions with Asp 120 and Asp 155 during the simulations.

Synthesis of proline-valine pseudodipeptide enol lactones, serine protease inhibitors

Pseudodipeptides of proline-valine that incorporate protio or halo enol lactone moieties have been synthesized from common acetylenic acid precursors; in each case, two diasteromers were prepared in enantiomerically pure form. The preparation began with isomeric propargylic alcohols derived from L-prolinal, which are further elaborated into the methyleneoxy valine pseudodipeptide analogues via an oxalactam intermediate. The pseudodipeptide acetylenic acids could by cyclized to the protio enol lactones by mercuric salts and could be elaborated to tetrapeptide analogues either before or after cyclization. The relative stability of the two diastereomeric enol lactone systems toward intramolecular acyl transfer could be rationalized by molecular mechanics energy calculations on ground-state and tetrahedral intermediates believed to be involved in the reaction. While the halo enol lactones derived from the pseudotetrapeptides proved to be very unstable, they could be prepared from the n-butyl carbamate derivatives of the dipeptide

Crystal and molecular structure of two geometrically restricted chemotactic tripeptides, analogues of formyl‐methionine‐leucine‐phenylalanine*

The crystal structures of HCO-Met-Leu-Phe-OC(CH3)3, (CH25H39N3O5S), fMLP-OtBu, and HCO-Met psi [CSNH]-Leu-Phe-OCH3, (C22H33N3O4S2), fMS LP-OMe, have been determined by single crystal X-ray diffraction, and their conformational properties investigated by molecular mechanics energy calculations. Crystals of fMLP-OtBu are monoclinic, space group P2(1), a = 12.027(4), b = 9.492(3), c = 12.660(4) A, beta = 101.99(3) degrees, Z = 2; those of fMS LP-OMe are orthorhombic, space group P2(1)2(1)2(1), a = 7.130(1), b = 12.097(2), c = 31.060(5) A, Z = 4. The first compounds fMLP-OtBu is the t-butyl ester of the tripeptide fMLP that represents one of the most potent compounds in inducing the lysozyme release from human neutrophils that reflects the chemotactic activity. From the crystal structure, it is shown that the orientation of the phenylalanine side chain is largely affected by the presence of the bulky group. fMSLP-OMe was shown to be inactive after thionation of the methionine residue in the original tripeptide. Nevertheless, the crystal structure does not reveal any influence of the presence of the thionated peptidic bond on the backbone conformation. The X-ray results have been used to generate parameters for empirical energy calculations. Subsequently, a strategy based on random generation of conformations followed by energy-minimization was applied to investigate the conformational space of thiopeptides, in comparison with normal peptides. From molecular free energy calculations, it is shown that the main influence of the introduction of a thioamide bond on the molecular structure is to prevent the existence of C7(eq) conformations involving the thiomethionine residue. Consequently, a larger number of conformers are found to form intramolecular hydrogen bonds involving the formyl group, reducing its availability to interact with the receptor. For the first time, the theoretical prediction of the existence of C7eq conformations for fMLP is made. The resulting conformers are compared to previously active structures of these chemotactic agents.

Macromodel—an integrated software system for modeling organic and bioorganic molecules using molecular mechanics

AbstractAn integrated molecular modeling system for designing and studying organic and bioorganic molecules and their molecular complexes using molecular mechanics is described. The graphically controlled, atom‐based system allows the construction, display and manipulation of molecules and complexes having as many as 10,000 atoms and provides interactive, state‐of‐the‐art molecular mechanics on any subset of up to 1,000 atoms. The system semiautomates the graphical construction and analysis of complex structures ranging from polycyclic organic molecules to biopolymers to mixed molecular complexes. We have placed emphasis on providing effective searches of conformational space by a number of different methods and on highly optimized molecular mechanics energy calculations using widely used force fields which are supplied as external files. Little experience is required to operate the system effectively and even novices can use it to carry out sophisticated modeling operations. The software has been designed to run on Digital Equipment Corporation VAX computers interfaced to a variety of graphics devices ranging from inexpensive monochrome terminals to the sophisticated graphics displays of the Evans & Sutherland PS300 series.

Conformational Features of DNA Containing aCis-SynPhotodimer

In an effort to understand the conformational and structural changes in DNA brought about by thymine photodimer, computer modeling and molecular mechanics energy calculations were performed on DNA hexamer and dodecamer duplexes containing a cis-syn photodimer. The conformation of the crystal structure of the cyanoethyl phosphate ester of the thymine dimer (Hruska et al., Biopolymers 25, 1399-1417 (1986)) was used in modeling the photodimer portion. Various starting conformations were used in the modeling procedure and the structures were minimized both retaining and later relaxing the crystallographic geometry of the cyclobutane ring. The results indicate that most of the deformation is restricted to the thymine dimer region, and that the conformational changes decrease rapidly on either side of the region containing the photodimer. The structural changes brought about by the introduction of the photodimer can be accommodated within six base paired duplex without significant bend in the DNA. More conformational changes are observed on the 5'-side of the photodimer than on the 3'-side. The conformational features, such as backbone torsion angles and sugar puckers, of the energy minimized structures are discussed in the context of the solution structures determined by NMR on a series of oligomers containing photodimers (Rycyna et al., Biochemistry 27, 3152-3163 (1988)).

A computergraphic investigation into the pharmacological role of the THC-cannabinoid phenolic moiety

There has been much debate as to the nature of the cannabinoid-receptor interaction, whether by traditional interpretation or by means of membrane perturbation. Whichever hypothesis is correct, the structural requirements for pharmacological action need determination. Here, we report a computergraphic investigation into the role of the phenolic hydroxyl moiety in such a receptor interaction. It has been determined by molecular mechanics energy calculations and volume map determinations that the proton of the hydroxyl group may be involved in hydrogen bonding at the putative receptor site.

Predicted mode of intercalation of doxorubicin with dinucleotide dimers

Intermolecular molecular mechanics energy calculations have been carried out for doxorubicin interacting with two dinucleotide dimer sequences. The preferred mode of intercalation is in the minor groove with the anthraquinone ring of the drug nearly perpendicular to the base pairs for the (CpG) sequence having alternate C3′ endo-C2′ endo sugar ring puckering. The preferred intercalation conformation of the drug is nearly identical to the N-bromacetyldaunomycin crystal structure. This prediction is qualitatively consistent with the recently reported crystal structure of a d(CpGpCpGpCpG) dimer-daunomycin complex. For the other dinucleotide sequence, (TpC-ApG), minor groove intercalation is also preferred, but the drug conformation can be changed.