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Composition-dependent energetic contribution of complex salt bridges to collagen stability.

ABSTRACT: Complex salt bridges, on which three or more charged residues interplay simultaneously, cannot be considered as addition of individual salt bridges. This is still an intriguing problem in protein folding and stability. Here, we used an obligated ABC-type collagen heterotrimer as a platform to study the relationship between energetic contributions and conformational details of three-body complex salt bridges anchored by positively charged residues, K and R. Eight complex salt bridges were constructed by engineering point mutations in the heterotrimer. The circular dichroism measurements showed that the K-anchored complex salt bridges were stronger than the R-anchored ones. The molecular dynamics simulation revealed that both types of salt bridges had distinct dynamic features. The energetic contribution of K-anchored salt bridges was mainly determined by strong single bridges. In the R-anchored complex salt bridges, both side-chain electrostatic interactions and side-chain-backbone hydrogen bonding were involved. An empirical equation was proposed to predict the energetic contributions with high accuracy (R² = 0.93). This work could help us take insights into the mechanisms of composition-dependent behaviors of the complex salt bridges on protein surface.

SUBMITTER: Sun T

PROVIDER: S-EPMC8391061 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Composition-dependent energetic contribution of complex salt bridges to collagen stability.

Sun Tiantian T Qiang Shumin S Lu Cheng C Xu Fei F

Biophysical journal 20210625 16

Complex salt bridges, on which three or more charged residues interplay simultaneously, cannot be considered as addition of individual salt bridges. This is still an intriguing problem in protein folding and stability. Here, we used an obligated ABC-type collagen heterotrimer as a platform to study the relationship between energetic contributions and conformational details of three-body complex salt bridges anchored by positively charged residues, K and R. Eight complex salt bridges were constru ...[more]

PMID: 34181903

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Project description:Protein thermal stability is an important factor considered in medical and industrial applications. Many structural characteristics related to protein thermal stability have been elucidated, and increasing salt bridges is considered as one of the most efficient strategies to increase protein thermal stability. However, the accurate simulation of salt bridges remains difficult. In this study, a novel method for salt-bridge design was proposed based on the statistical analysis of 10,556 surface salt bridges on 6,493 X-ray protein structures. These salt bridges were first categorized based on pairing residues, secondary structure locations, and Cα-Cα distances. Pairing preferences generalized from statistical analysis were used to construct a salt-bridge pair index and utilized in a weighted electrostatic attraction model to find the effective pairings for designing salt bridges. The model was also coupled with B-factor, weighted contact number, relative solvent accessibility, and conservation prescreening to determine the residues appropriate for the thermal adaptive design of salt bridges. According to our method, eight putative salt-bridges were designed on a mesophilic β-glucosidase and 24 variants were constructed to verify the predictions. Six putative salt-bridges leaded to the increase of the enzyme thermal stability. A significant increase in melting temperature of 8.8, 4.8, 3.7, 1.3, 1.2, and 0.7°C of the putative salt-bridges N437K-D49, E96R-D28, E96K-D28, S440K-E70, T231K-D388, and Q277E-D282 was detected, respectively. Reversing the polarity of T231K-D388 to T231D-D388K resulted in a further increase in melting temperatures by 3.6°C, which may be caused by the transformation of an intra-subunit electrostatic interaction into an inter-subunit one depending on the local environment. The combination of the thermostable variants (N437K, E96R, T231D and D388K) generated a melting temperature increase of 15.7°C. Thus, this study demonstrated a novel method for the thermal adaptive design of salt bridges through inference of suitable positions and substitutions.

Dataset Information

Composition-dependent energetic contribution of complex salt bridges to collagen stability.

Publications

Composition-dependent energetic contribution of complex salt bridges to collagen stability.

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