non-Gly Residues Research Articles

Spurious correlations in research on the effects of specific cognitive abilities

Studies on the effect of non-g ability residuals have often employed double adjustment for general cognitive ability (g), as they have calculated the ability residuals adjusting for g and then calculated the effect of the non-g residuals while adjusting for g. The present simulations demonstrate that the double adjustments may result in spurious negative associations between the non-g residual on one cognitive ability, e.g. verbal ability, and variables with a positive association with another ability, e.g. SAT math and math ability. In analyses of data from the 1997 National Longitudinal Survey of Youth (NLSY97), the negative associations between non-g residuals on verbal and math ability and aptitude test scores on the other ability vanished when not double adjusting for g. This indicates that the observed negative associations may be spurious and not due to differential investment of time and effort in one ability at the expense of the other ability, as suggested in the literature. Researchers of the effects of specific abilities are recommended to validate their findings and interpretations with analyses not double adjusting for g.

The characterization of Thermotoga maritima Arginine Binding Protein variants demonstrates that minimal local strains have an important impact on protein stability

The Ramachandran plot is a versatile and valuable tool that provides fundamental information for protein structure determination, prediction, and validation. The structural/thermodynamic effects produced by forcing a residue to adopt a conformation predicted to be forbidden were here explored using Thermotoga maritima Arginine Binding Protein (TmArgBP) as model. Specifically, we mutated TmArgBP Gly52 that assumes a conformation believed to be strictly disallowed for non-Gly residues. Surprisingly, the crystallographic characterization of Gly52Ala TmArgBP indicates that the structural context forces the residue to adopt a non-canonical conformation never observed in any of the high-medium resolution PDB structures. Interestingly, the inspection of this high resolution structure demonstrates that only minor alterations occur. Nevertheless, experiments indicate that Gly52 replacements in TmArgBP produce destabilizations comparable to those observed upon protein truncation or dissection in domains. Notably, we show that force-fields commonly used in computational biology do not reproduce this non-canonical state. Using TmArgBP as model system we here demonstrate that the structural context may force residues to adopt conformations believed to be strictly forbidden and that barely detectable alterations produce major destabilizations. Present findings highlight the role of subtle strains in governing protein stability. A full understanding of these phenomena is essential for an exhaustive comprehension of the factors regulating protein structures.

General Intelligence (g), ACT Scores, and Theory of Mind: (ACT)g Predicts Limited Variance Among Theory of Mind Tests

This study is the first to examine relations between general intelligence (g), non-g factors, and theory of mind (ToM) using structural equation modeling with multiple indicators of g and ToM. g was based on the subtests of the ACT, a college admissions test that is strongly g loaded, and ToM was based on the Reading the Mind in the Eyes Test and the Short Story Test (SST). g correlated strongly with a latent ToM factor (β = .65) and moderately with the two ToM tests (β ≈ .34), which correlated modestly with each other (β = .27). The modest correlation between the ToM tests indicates that g predicted a small amount of variance among the ToM tests (7%) and suggests that the ToM tests had little in common. In addition, non-g residuals of the ACT subtests, obtained after removing g, correlated negligibly with the ToM factor and the ToM tests (|β| < 0.06). Similar results were obtained for the ToM residuals, which correlated trivially with the ACT subtests. The trivial non-g effects suggest that g-ToM relations were attributable to “not much more than g.” The results replicated with different combinations of ACT subtests, controls for possible confounds (reading comprehension on the SST), and another college admissions test (the SAT). The use of a convenience sample (college students) and the limited measures of g and ToM are discussed as limitations. Future research should examine the robustness of effects using different measures of g and ToM and also examine possible mediators of g-ToM relations (e.g., executive functions).

Non-g Factors Predict Educational and Occupational Criteria: More than g.

In a prior issue of the Journal of Intelligence, I argued that the most important scientific issue in intelligence research was to identify specific abilities with validity beyond g (i.e., variance common to mental tests) (Coyle, T.R. Predictive validity of non-g residuals of tests: More than g. Journal of Intelligence 2014, 2, 21–25.). In this Special Issue, I review my research on specific abilities related to non-g factors. The non-g factors include specific math and verbal abilities based on standardized tests (SAT, ACT, PSAT, Armed Services Vocational Aptitude Battery). I focus on two non-g factors: (a) non-g residuals, obtained after removing g from tests, and (b) ability tilt, defined as within-subject differences between math and verbal scores, yielding math tilt (math > verbal) and verbal tilt (verbal > math). In general, math residuals and tilt positively predict STEM criteria (college majors, jobs, GPAs) and negatively predict humanities criteria, whereas verbal residuals and tilt show the opposite pattern. The paper concludes with suggestions for future research, with a focus on theories of non-g factors (e.g., investment theories, Spearman’s Law of Diminishing Returns, Cognitive Differentiation-Integration Effort Model) and a magnification model of non-g factors.

Non-g residuals of group factors predict ability tilt, college majors, and jobs: A non-g nexus

This study examined the predictive power of non-g residuals of group factors (based on multiple tests) for diverse criteria (e.g., aptitude tests, college majors, occupations). Test scores were drawn from the National Longitudinal Survey of Youth (N=1950). Four group factors (math, verbal, speed, shop/technical) were estimated using the Armed Services Vocational Aptitude Battery, a diverse battery of 12 cognitive tests. The residuals of the group factors were estimated after removing g (variance common to all tests) and were correlated with aptitude test scores (SAT, ACT, PSAT), ability tilt (i.e., difference between math and verbal scores on the aptitude tests), and college majors and jobs in science, technology, engineering, and math (STEM) and the humanities. The math residuals correlated positively with math/STEM criteria and negatively with verbal/humanities criteria. In contrast, the verbal residuals showed the opposite pattern. The residuals of the two non-academic factors (speed and shop) generally correlated negligibly with all criteria. The results are the first to demonstrate the predictive power of group factor residuals for diverse criteria. The findings extend prior research on non-g factors for individual tests (SAT and ACT) and provide evidence of a non-g nexus involving group factors. The pattern of results supports investment theories, which predict that investment in one area (math) correlates positively with complementary criteria (math/STEM) but negatively with competing criteria (verbal/humanities).

Do non-g factors of cognitive ability tests align with specific academic achievements? A combined bifactor modeling approach

Bifactor models can clarify how general and specific intelligence factors relate to general and specific academic achievements. By modeling specific group factors that are orthogonal to the general factors one can establish systematic correlations between corresponding non-g residuals of general intelligence and achievement factors. Using data from the National Longitudinal Survey of Youth 1997 (NLSY97; n=2155), bifactor models were estimated for cognitive ability tests (intelligence, scholastic aptitude) and high school grade point averages (GPA), presuming group factors for numeric/mathematics and for verbal/language content, respectively. The three general factors (intelligence, scholastic aptitude, GPA) were highly correlated. The group factors evidenced convergent validity for numeric abilities and mathematics achievement; the remaining group factor correlations were small. The results demonstrate that besides substantial correlations of the general factors, specific non-g abilities can be successfully linked to specific group factors of academic achievement.

SAT non-g residuals predict course specific GPAs: Support for investment theory

This research examined relations of SAT residuals, obtained after removing g, with first-year course specific college GPAs (grade point averages) from the SAT Validity Study (N=160,670). g was based on SAT scores and GPAs in two areas: science, technology, engineering, and math (STEM), and the humanities (e.g., English, art, history, foreign languages). The results revealed a domain specific pattern of effects: SAT math residuals correlated positively with math and STEM GPAs and negatively with verbal and humanities GPAs, whereas SAT verbal (reading and writing) residuals showed the opposite pattern of effects. The pattern of effects replicated with manifest GPAs and latent GPAs, with and without missing data, and with different STEM and humanities GPAs. The largest effects were obtained for models with either the SAT reading or writing subtest and with latent GPAs (absolute β≈.17). The difference between residual effects for math and verbal GPAs was medium in size (mean difference≈.27). The results supported investment theories, which predict that investment in a specific ability (math) boosts similar abilities but retards competing abilities (verbal). The findings are the first to confirm the predictions of investment theory with course specific GPAs.

Predictive Validity of Non-g Residuals of Tests: More Than g

This comment argues that an important issue in intelligence research is to identify constructs with validity beyond g, and that non-g residuals of tests represent a promising target.

Sparsely populated residue conformations in protein structures: Revisiting “experimental” Ramachandran maps

The Ramachandran map clearly delineates the regions of accessible conformational (φ-ψ) space for amino acid residues in proteins. Experimental distributions of φ, ψ values in high-resolution protein structures, reveal sparsely populated zones within fully allowed regions and distinct clusters in apparently disallowed regions. Conformational space has been divided into 14 distinct bins. Residues adopting these relatively rare conformations are presented and amino acid propensities for these regions are estimated. Inspection of specific examples in a completely "arid", fully allowed region in the top left quadrant establishes that side-chain and backbone interactions may provide the energetic compensation necessary for populating this region of φ-ψ space. Asn, Asp, and His residues showed the highest propensities in this region. The two distinct clusters in the bottom right quadrant which are formally disallowed on strict steric considerations correspond to the gamma turn (C7 axial) conformation (Bin 12) and the i + 1 position of Type II' β turns (Bin 13). Of the 516 non-Gly residues in Bin 13, 384 occupied the i + 1 position of Type II' β turns. Further examination of these turn segments revealed a high propensity to occur at the N-terminus of helices and as a tight turn in β hairpins. The β strand-helix motif with the Type II' β turn as a connecting element was also found in as many as 57 examples.

Non-g residuals of the SAT and ACT predict specific abilities

This research examined whether non-g residuals of the SAT and ACT subtests, obtained after removing g, predicted specific abilities. Non-g residuals of the verbal and math subtests of the SAT and ACT were correlated with academic (verbal and math) and non-academic abilities (speed and shop), both based on the Armed Services Vocational Aptitude Battery. Non-g residuals of the SAT and ACT math subtests were positively related to math ability and negatively to verbal ability, whereas the opposite pattern was found for the verbal subtests. Non-g residuals of both sets of subtests were weakly related to non-academic abilities. The results support an investment theory of skills and abilities: Investing in skills in one area (e.g., math) improves abilities in that area but lowers abilities in competing areas (e.g., verbal).

Solution Structure of Human Peptidyl Prolyl Isomerase-like Protein 1 and Insights into Its Interaction with SKIP

The human PPIL1 (peptidyl prolyl isomerase-like protein 1) is a specific component of human 35 S U5 small nuclear ribonucleoprotein particle and 45 S activated spliceosome. It is recruited by SKIP, another essential component of 45 S activated spliceosome, into spliceosome just before the catalytic step 1. It stably associates with SKIP, which also exists in 35 S and activated spliceosome as a nuclear matrix protein. We report here the solution structure of PPIL1 determined by NMR spectroscopy. The structure of PPIL1 resembles other members of the cyclophilin family and exhibits PPIase activity. To investigate its interaction with SKIP in vitro, we identified the SKIP contact region by GST pulldown experiments and surface plasmon resonance. We provide direct evidence of PPIL1 stably associated with SKIP. The dissociation constant is 1.25 x 10(-7) M for the N-terminal peptide of SKIP-(59-129) with PPIL1. We also used chemical shift perturbation experiments to show the possible SKIP binding interface on PPIL1. These results illustrated that a novel cyclophilin-protein contact mode exists in the PPIL1-SKIP complex during activation of the spliceosome. The biological implication of this binding with spliceosome rearrangement during activation is discussed.

Conformational Features of a Natural Break in the Type IV Collagen Gly-X-Y Repeat

Fibrillar collagens have an absolute requirement for Gly as every 3rd residue, whereas breaks in the Gly-X-Y repeating pattern are found normally in the triple helix domains of non-fibrillar collagens, such as type IV collagen in basement membranes. In this study, a model 30-mer peptide is designed to include the interruption GPOGAAVMGPOGPO found in the alpha5 chain of type IV collagen. The GAAVM peptide forms a stable triple helix, with Tm= 29 degrees C. When compared with a control peptide with Gly as every 3rd residue, the GAAVM peptide has a marked decrease in the 225 nm maximum of its CD spectrum and a 10 degrees C drop in stability. A 50% decrease in calorimetric enthalpy is observed, which may result from disruption of ordered water structure anchored by regularly placed backbone carbonyls. NMR studies on specific 15N-labeled residues within the GAAVM peptide indicate a normal triple helical structure for Gly-Pro-Hyp residues flanking the break. The sequence within the break is not disordered but shows altered hydrogen exchange rates and an abnormal Val chemical shift. It was previously reported that a peptide designed to model a similar kind of interruption in the peptide (Pro-Hyp-Gly)10, (GPOGPOPOGPO), is unable to form a stable triple helix, and replacement of GAA by GPO or VM by PO within the GAAVM break decreases the stability. Thus, rigid imino acids are unfavorable within a break, despite their favorable stabilization of the triple helix itself. These results suggest some non-random structure typical of this category of breaks in the Gly-X-Y repeat of the triple helix.

Solution Structure of Prosurvival Mcl-1 and Characterization of Its Binding by Proapoptotic BH3-only Ligands

The B cell lymphoma-2 (Bcl-2) homologs myeloid cell leukemia-1 (Mcl-1) and A1 are prosurvival factors that selectively bind a subset of proapoptotic Bcl homology (BH) 3-only proteins. To investigate the molecular basis of the selectivity, we determined the solution structure of the C-terminal Bcl-2-like domain of Mcl-1. This domain shares features expected of a prosurvival Bcl-2 protein, having a helical fold centered on a core hydrophobic helix and a surface-exposed hydrophobic groove for binding its cognate partners. A number of residues in the binding groove differentiate Mcl-1 from its homologs, and in contrast to other Bcl-2 homologs, Mcl-1 has a binding groove in a conformation intermediate between the open structures characterized by peptide complexes and the closed state observed in unliganded structures. Mutagenesis of potential binding site residues was used to probe the contributions of groove residues to the binding properties of Mcl-1. Although mutations in Mcl-1 had little impact on binding, a single mutation in the BH3-only ligand Bad enabled it to bind both Mcl-1 and A1 while retaining its binding to Bcl-2, Bcl-xL, and Bcl-w. Elucidating the selective action of certain BH3-only ligands is required for delineating their mode of action and will aid the search for effective BH3-mimetic drugs.

Identification of a Key Structural Element for Protein Folding Within β-Hairpin Turns

Specific residues in a polypeptide may be key contributors to the stability and foldability of the unique native structure. Identification and prediction of such residues is, therefore, an important area of investigation in solving the protein folding problem. Atypical main-chain conformations can help identify strains within a folded protein, and by inference, positions where unique amino acids may have a naturally high frequency of occurrence due to favorable contributions to stability and folding. Non-Gly residues located near the left-handed α-helical region (L-α) of the Ramachandran plot are a potential indicator of structural strain. Although many investigators have studied mutations at such positions, no consistent energetic or kinetic contributions to stability or folding have been elucidated. Here we report a study of the effects of Gly, Ala and Asn substitutions found within the L-α region at a characteristic position in defined β-hairpin turns within human acidic fibroblast growth factor, and demonstrate consistent effects upon stability and folding kinetics. The thermodynamic and kinetic data are compared to available data for similar mutations in other proteins, with excellent agreement. The results have identified that Gly at the i+3 position within a subset of β-hairpin turns is a key contributor towards increasing the rate of folding to the native state of the polypeptide while leaving the rate of unfolding largely unchanged.

Role of non-glycine residues in left-handed helical conformation for the conformational stability of human lysozyme.

To understand the role of non-Gly residues in the left-handed helical conformation for the conformational stability of a protein, the non-Gly to Gly and Ala mutations at six left-handed residues (R21, Y38, R50, Q58, H78, and N118) of the human lysozyme were examined. The thermodynamic parameters for denaturation were determined using a differential scanning calorimeter, and the crystal structures were analyzed by X-ray crystallography. If a left-handed non-Gly had an unfavorable steric interaction between the side-chain Cbeta and backbone, the Gly mutation would be expected to stabilize more than the Ala mutation at the same position. For the mutant human lysozymes, however, there were few differences in the denaturation Gibbs energy (DeltaG) between the Gly and Ala mutants, except for the substitution at position 58. Analysis of the changes in stability (DeltaDeltaG) based on the structures of the wild-type and mutant proteins showed that the experimental DeltaDeltaG value of Q58G was approximately 7 kJ/mol higher than the estimated value without consideration of any local steric interaction. These results indicate that only Q58G increased the stability by elimination of local constraints. The residue 58 is located at the most rigid position in the left-handed non-Gly residues and is involved in its enzymatic function. It can be concluded that the left-handed non-Gly residues do not always have unfavorable strain energies as compared with Gly at the same position.

Role of Amino Acid Residues at Turns in the Conformational Stability and Folding of Human Lysozyme,

To clarify the role of amino acid residues at turns in the conformational stability and folding of a globular protein, six mutant human lysozymes deleted or substituted at turn structures were investigated by calorimetry, GuHCl denaturation experiments, and X-ray crystal analysis. The thermodynamic properties of the mutant and wild-type human lysozymes were compared and discussed on the basis of their three-dimensional structures. For the deletion mutants, Delta47-48 and Delta101, the deleted residues are in turns on the surface and are absent in human alpha-lactalbumin, which is homologous to human lysozyme in amino acid sequence and tertiary structure. The stability of both mutants would be expected to increase due to a decrease in conformational entropy in the denatured state; however, both proteins were destabilized. The destabilizations were mainly caused by the disappearance of intramolecular hydrogen bonds. Each part deleted was recovered by the turn region like the alpha-lactalbumin structure, but there were differences in the main-chain conformation of the turn between each deletion mutant and alpha-lactalbumin even if the loop length was the same. For the point mutants, R50G, Q58G, H78G, and G37Q, the main-chain conformations of these substitution residues located in turns adopt a left-handed helical region in the wild-type structure. It is thought that the left-handed non-Gly residue has unfavorable conformational energy compared to the left-handed Gly residue. Q58G was stabilized, but the others had little effect on the stability. The structural analysis revealed that the turns could rearrange the main-chain conformation to accommodate the left-handed non-Gly residues. The present results indicate that turn structures are able to change their main-chain conformations, depending upon the side-chain features of amino acid residues on the turns. Furthermore, stopped-flow GuHCl denaturation experiments on the six mutants were performed. The effects of mutations on unfolding-refolding kinetics were significantly different among the mutant proteins. The deletion/substitutions in turns located in the alpha-domain of human lysozyme affected the refolding rate, indicating the contribution of turn structures to the folding of a globular protein.

Disallowed Ramachandran Conformations of Amino Acid Residues in Protein Structures

An analysis of the nature and distribution of disallowed Ramachandran conformations of amino acid residues observed in high resolution protein crystal structures has been carried out. A data set consisting of 110 high resolution, non-homologous, protein crystal structures from the Brookhaven Protein Data Bank was examined. The data set consisted of a total of 18,708 non-Gly residues, which were characterized on the basis of their backbone dihedral angles (φ, ψ). Residues falling outside the defined “broad allowed limits” on the Ramachandran map were chosen and the reported B-factor value of the α-carbon atom was used to further select well defined disallowed conformations. The conformations of the selected 66 disallowed residues clustered in distinct regions of the Ramachandran map indicating that specific φ, ψ angle distortions are preferred under compulsions imposed by local constraints. The distribution of various amino acid residues in the disallowed residue data set showed a predominance of small polar/charged residues, with bulky hydrophobic residues being infrequent. As a further check, for all the 66 cases non-hydrogen van der Waals short contacts in the protein structures were evaluated and compared with the ideal “Ala-dipeptide” constructed using disallowed dihedral angle (φ, ψ) values. The analysis reveals that short contacts are eliminated in most cases by local distortions of bond angles. An analysis of the conformation of the identified disallowed residues in related protein structures reveals instances of conservation of unusual stereochemistry.