| Summary: | Noncovalent interactions play a pivotal role in regulating protein conformation, stability and dynamics. Among the quantum mechanical (QM) overlap-based noncovalent interactions, <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mi>n</mi><mo>→</mo><msup><mi>π</mi><mo>*</mo></msup></mrow></semantics></math></inline-formula> is the best understood with studies ranging from small molecules to <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>β</mi></semantics></math></inline-formula>-turns of model proteins such as GB1. However, these investigations do not explore the interplay between multiple overlap interactions in contributing to local structure and stability. In this work, we identify and characterize all noncovalent overlap interactions in the <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>β</mi></semantics></math></inline-formula>-turn, an important secondary structural element that facilitates the folding of a polypeptide chain. Invoking a QM framework of natural bond orbitals, we demonstrate the role of several additional interactions such as <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mi>n</mi><mo>→</mo><msup><mi>σ</mi><mo>*</mo></msup></mrow></semantics></math></inline-formula> and <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mi>π</mi><mo>→</mo><msup><mi>π</mi><mo>*</mo></msup></mrow></semantics></math></inline-formula> that are energetically comparable to or larger than <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mi>n</mi><mo>→</mo><msup><mi>π</mi><mo>*</mo></msup></mrow></semantics></math></inline-formula>. We find that these interactions are sensitive to changes in the side chain of the residues in the <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>β</mi></semantics></math></inline-formula>-turn of GB1, suggesting that the <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mi>n</mi><mo>→</mo><msup><mi>π</mi><mo>*</mo></msup></mrow></semantics></math></inline-formula> may not be the only component in dictating <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>β</mi></semantics></math></inline-formula>-turn conformation and stability. Furthermore, a database search of <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mi>n</mi><mo>→</mo><msup><mi>σ</mi><mo>*</mo></msup></mrow></semantics></math></inline-formula> and <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mi>π</mi><mo>→</mo><msup><mi>π</mi><mo>*</mo></msup></mrow></semantics></math></inline-formula> in the PDB reveals that they are prevalent in most proteins and have significant interaction energies (∼1 kcal/mol). This indicates that all overlap interactions must be taken into account to obtain a comprehensive picture of their contributions to protein structure and energetics. Lastly, based on the extent of QM overlaps and interaction energies, we propose geometric criteria using which these additional interactions can be efficiently tracked in broad database searches.
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