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. 2022 Nov 18;7(48):43492–43498. doi: 10.1021/acsomega.2c03934

Effect of Secondary Structures on the Adsorption of Peptides onto Hydrophobic Solid Surfaces Revealed by SALDI-TOF and MD Simulations

Young Hyun No †, Nam Hyeong Kim †, Muhammad Shahzad Zafar ‡,§, Seon Hwa Park ∥, Jaecheol Lee ⊥,#,¶,∇, Heeyeop Chae ‡, Wan Soo Yun ∥,*, Young Dok Kim ∥,*, Yong Ho Kim †,∥,¶,○,*
PMCID: PMC9730778  PMID: 36506148

Abstract

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The adsorption of peptides and proteins on hydrophobic solid surfaces has received considerable research attention owing to their wide applications to biocompatible nanomaterials and nanodevices, such as biosensors and cell adhesion materials with reduced nanomaterial toxicity. However, fundamental understandings about physicochemical hydrophobic interactions between peptides and hydrophobic solid surfaces are still unknown. In this study, we investigate the effect of secondary structures on adsorption energies between peptides and hydrophobic solid surfaces via experimental and theoretical analyses using surface-assisted laser desorption/ionization-time-of-flight (SALDI-TOF) and molecular dynamics (MD) simulations. The hydrophobic interactions between peptides and hydrophobic solid surfaces measured via SALDI-TOF and MD simulations indicate that the hydrophobic interaction of peptides with random coil structures increased more than that of peptides with an α-helix structure when polar amino acids are replaced with hydrophobic amino acids. Additionally, our study sheds new light on the fundamental understanding of the hydrophobic interaction between hydrophobic solid surfaces and peptides that have diverse secondary structures.

Introduction

The study on hydrophobic interactions of peptides on inorganic surfaces is critical in the field of materials science. Recently, based on the knowledge of these interactions, several adaptable biocompatible materials have been developed for use in biosensors.1−100 Moreover, novel materials can be realized using these interactions for applications, such as antimicrobial efficiency,4 water treatment,5 and biomedical application.6−8 Due to its ever-increasing application, several researchers have tried to understand the effects of several factors on the adsorption of proteins/peptides onto hydrophobic surfaces, namely, solution pH, temperature, molecular weight, isoelectric point, and chemical properties.9−13 However, not only the peptide sequence but also the secondary structure, along with the surface properties, such as topography, roughness, and surface chemistry, plays a key role when a peptide is docked onto a hydrophobic surface.14−101 For the effective stabilization of a protein, the effect of the presence of a physical surface plays a key role in reducing the entropy of the unfolded state.20−24 To address this aspect, researchers have studied the interactions to adsorption on a solid surface using naturally existing proteins, such as BSA,25 lysozyme,26 and peptide-like PLL.23 The common rationale for their selection was a specific type of protein or peptide with inherent mixed structures of α-helix and β-sheets, which limits the scope of the study. Furthermore, there are controversial discussions related to the effect of secondary structures for interaction with hydrophobic surfaces. Some researchers observed that α-helix represented more robust structural properties for interaction with hydrophobic surfaces than β-sheets in lysozymes.27 In contrast, some researchers studied that β-sheets were stiffer structural units compared to α-helix on the graphene surface.28 For better understanding of the structure and dynamics of interfacial peptides, experimental techniques such as vibrational sum frequency generation spectroscopy have also been developed.29,30 However, the effect of a random coil structure for hydrophobic interactions and how the interactions can be modulated when the sequence is changed with specific secondary structures are still largely unknown.

In this paper, we report the effect of secondary structures on hydrophobic interactions between peptides and hydrophobic solid surfaces with experimental and theoretical analyses using surface-assisted laser desorption/ionization-time-of-flight (SALDI-TOF) and molecular dynamics (MD) simulations. The peptides were modulated by adjusting the number of amino acids to observe the effect of secondary structures on hydrophobic interactions when the peptide sequence is mutated from polar amino acids to hydrophobic amino acids. Specifically, we increased the α-helix structural stability by extending the length of peptides and the hydrophobicity of peptides mutating polar amino acids (E; glutamic acid) into hydrophobic amino acids (I; isoleucine). To measure the hydrophobic interactions between peptides and hydrophobic solid surfaces, we designed an inorganic matrix that can be used to measure hydrophobic interactions with SALDI-TOF principle using polydimethylsiloxane (PDMS)-coated TiO2 nanoparticles. Subsequently, to calculate the peptide-PDMS binding energy when modulated peptides bind to PDMS, we performed MD simulations. Our results showed that the mutations in peptides with a random coil structure are more effective in hydrophobic interactions with PDMS than mutations in peptides with an α-helix structure.

Methods

Peptide Synthesis

The peptide candidates were synthesized by the Fmoc chemistry-based H-Rink amide ChemMatrix resin (0.1 mmol, 14 synthesis scale, 0.53 mmol/g substitution value, PCAS BioMatrix Inc.) by a manual solid-phase peptide synthesizer. Before starting the synthesis, the resin was swelled in N,N-dimethylformamide (DMF) for 30 min. The Fmoc amino acid was deported by the deprotecting solution (piperidine 20% and DMF 80%) and coupled with the activated amino acid (HBTU and DIEA) at 75 ± 5 °C for 5 and 7 min, respectively, with alternating steps of washing with DMF and dichloromethane three times after every deprotecting and coupling step. The different lengths of PBP-7aa, PBP-14aa, and PBP-21aa were cleaved from the solid support by the cleavage solution containing trifluoroacetic acid (TFA)/triisopropylsilane/H2O (95:2.5:2.5). At room temperature, the solution was stirred for 2 h. After stirring, the cleavage solute was filtered for separation from the resin, and the solvent was evaporated under the flow of N2 gas. Afterward, the crude peptides were precipitated in cold diethyl ether and lyophilized with powder.

Peptide Purification and Confirmation of Mass

The PBP peptide candidates were purified on high-performance liquid chromatography (HPLC, Agilent) by using a C4 column (Agilent) in mobile-phase solutions of A (100% DI water and 0.1% TFA) and stationary-phase solutions of B (90% ACN, 10% distilled water, and 0.1% TFA). The gradients were set at 10% during 10 min, 70% during 70 min, and 100% during 75 min 10%—80 min with a 1%/min rate. The molecular mass of all peptides was confirmed by matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) mass spectrometry using a Bruker Micro Ultra flex III mass spectrometer (flex control 1.01).

Preparation of PDMS-Coated TiO2 Nanoparticles

The TiO2 nanoparticles coated with PDMS were synthesized by the thermal deposition method. The PDMS-coated TiO2 surface was characterized using FT-IR adsorption spectra (Vertex 70 series, Bruker Korea) and subjected to test at a 4 cm–1 resolution. The X-ray diffraction patterns of bare TiO2 and PDMS-coated TiO2 surfaces were recorded on a diffractometer. For the optical absorption arrangement of bare TiO2 and PDMS-coated TiO2 nanoparticles, the ultraviolet–visible (UV–vis) absorption spectra of both samples were obtained in the reflection mode. The matrix solutions for SALDI-TOF measurements were prepared by dispersing 0.05 g of bare TiO2 or PDMS-coated TiO2 nanoparticle powder in 10 mL of 99% ethanol. Each solution was bath-sonicated for 90 min at 100% power. The solution was placed overnight, and a supernatant was selected to be used as the SALDI-TOF matrix.

Measurement of SALDI-TOF

SALDI-TOF MS measurements were performed in positive-ion and reflection modes by using an Ultra flex III mass spectrometer (Bruker Daltonics) equipped with a 337 nm pulsed nitrogen laser. The applied acceleration voltage was +20 kV to obtain high resolution and high signal-to-noise (S/N) ratio; each mass spectrum was generated by an average of 200 laser pulses. We measured the same spot five times to obtain the average and standard deviation of the intensity. The signal intensity of SALDI-TOF MS was obtained at 30% of maximum laser power by using the CHCA organic matrix and 40% of maximum laser power when using the TiO2 matrix and the PDMS-coated TiO2 matrix. Data processing was performed with the Flex analysis 3.0 software.

MD Simulations

To simulate the molecular adsorption of PBP peptide candidates on the PDMS surface, we carried out all-atom MD simulations with explicit water by using the NAMD package with the CHARMM36m force field.31 The initial structure is constructed with PDMS and peptides whose secondary structure is known as a helix reported in the protein data bank (PDB) with a PDB code of 3S0R. The peptide sequences were truncated and mutated to understand the effects of the secondary structure to the hydrophobic interaction. The force field parameters of PDMS were added based on a previous research.16,32 To construct a PDMS substrate, we first pre-equilibrated a single chain of PDMS for 10 ns. We extracted 12 conformations of PDMS on the last 2.4 ns trajectory with an interval of 200 ps, and they were positioned in a layer into a plate of 50 × 50 × 13 Å3 to construct a stable PDMS substrate. We performed equilibrium MD simulations of a layer PDMS with explicit water using periodic boundary conditions for 10 ns. The modulated peptide candidates were positioned on top of the PDMS substrate with a height of 5 Å. An explicit solvent box was constructed with a TIP3P water model. After 103 energy minimization steps, the equilibrium dynamic simulation was implemented based on the NPT ensemble at 310 K for 500 ns. The time step was 2 fs/step for rigid bond simulation, and the trajectory was recorded every 10 ps. The binding energies between the peptide and PDMS surface was calculated with the molecular mechanics-Poisson–Boltzmann surface area (MM-PBSA) method. MM-PBSA is described as

graphic file with name ao2c03934_m001.jpg

where ΔEMM is the molecular mechanics energy, ΔGnp is the nonpolar solvation energy, and ΔGPB is the polar solvation energy. The entropy contribution can be omitted due to the relative binding energy. When we want to calculate the relative binding energies of some peptides that have a similar structure and binding modes, the entropy contribution can be omitted. We calculated only ΔEMM, ΔGnp, and ΔGPB energies.

Results and Discussion

Modulation of Peptides Varying Secondary Structure and Hydrophobicity

To understand the effect of the secondary structure of the peptide on its adsorption onto a hydrophobic surface, the peptide candidates were constructed for controlling the structural stability of α-helix and hydrophobicity of peptides (Table 1). From the same sequence of a peptide with α-helix secondary structure, the structural stability was controlled by a change in the number of amino acids. As the number of amino acids increased, the α-helix secondary structure became more stable. For example, seven amino acid length peptides are too short to form an α-helix secondary structure, so they mainly represent a random coil structure (Figure S1A). In contrast, the 14 and 21 amino acid length peptides can form an α-helix secondary structure, but the helicity of the 14 amino acid length peptide is lower than that of the 21 amino acid length peptides (Figure S1B,C). By mutating the polar amino acid (E, Glu) to a hydrophobic amino acid (I, Ile), the same hydrophobicity for each peptide candidate was increased (1.143) for more hydrophobic interactions with PDMS. To minimize the mass effect, the mutation was performed in amino acids that have a similar molecular weight (Glu: 129.12 g/mol and Ile: 113.16 g/mol) per seven amino acids.

Table 1. In the same sequence, the structure was controlled by change in length by mutating the charged residue (E, Glu) to a hydrophobic residue (I, Ile), and mutation is performed once per seven residuesa.

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a

Comparison was proceeded for two peptides, which have the same difference of hydrophobicity (1.143).

Since isoleucine was substituted for glutamic acid, the hydrophobicity was expected to increase, along with the net charge of the peptide, as a nonpolar amino acid was substituted with a negatively charged amino acid. To confirm whether hydrophobicity can be modulated by isoleucine mutation, HPLC was utilized. Figure 1A shows the hydrophobicity change of peptides after mutation measured by HPLC, which can be compared with the hydrophobicity based on retention time. The HPLC retention time measured by HPLC and the theoretical hydrophobicity had a similar tendency, which implies that our peptide candidate is properly constructed (Figure S2).

Figure 1.

Figure 1

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Affinity of hydrophobic modulated peptides to the surface-modified solid matrix using SALDI-MS, whose signal intensity represents the interaction strength which increases depending on the binding affinity. (A) Hydrophobicity measured by HPLC retention time and theoretical hydrophobicity. (B-D) Analysis of SALDI-TOF MS using the TiO2-based matrix in hydrophobicity dependence. Peptide’s mass is (B) <1000 Da (PBP-7aa), (C) >1000 Da (PBP-14aa), and (D) >2000 Da (PBP-21aa).

Development of a PDMS-Coated Matrix for the Study of Hydrophobic Interactions

To measure the hydrophobic interaction between peptides and PDMS, an inorganic solid matrix that consists of PDMS-coated TiO2 for laser desorption/ionization and hydrophobic interaction with peptides was developed. TiO2 nanoparticles are used due to their efficiency in the ionization and desorption process of peptides by transferring the charge and energy from a laser to peptides. To observe the binding effect between hydrophobic surfaces and peptides, PDMS was thinly coated onto TiO2 nanoparticles at a 1.5 nm depth by the thermal deposition method. It is important to coat a thin PDMS layer because the energy must be transferred from the TiO2 nanoparticles. If the thickness of the PDMS layer is >4 nm, the efficiency of energy transfer decreases rapidly. To confirm the surface properties of PDMS-coated TiO2 nanoparticles, transmission electron microscopy (TEM), Fourier transform infrared (FT-IR) spectroscopy, UV–vis absorption, and X-ray diffraction patterns were measured (Figure S3). The TEM images indicated a thin layer of PDMS with 1.5 nm adsorbed onto the TiO2 nanoparticle surface (Figure S3B). These data represent local geometric information; the size of the bare TiO2 nanoparticle was around 15 nm and that of the PDMS-coated TiO2 nanoparticle was around 18–20 nm due to a thin PDMS layer of 1.5 nm. The functional group of the PDMS-coated TiO2 nanoparticle surface differs from that of the bare TiO2 nanoparticle surface. The surface modification of the TiO2 nanoparticle by PDMS was confirmed by FT-IR spectra, as shown in Figure S3C. The FT-IR spectra of the PDMS-coated TiO2 nanoparticle surface show sharp peaks at 2964 and 1100 cm–1, corresponding to the asymmetric stretching of CH3 and Si–O–Si, respectively. The peak at 1261 cm–1 is due to the symmetric deformation of the Si–CH3 frequency of PDMS. The bending peak at 1630 cm–1 of H–O–H corresponds to a hydrophilic surface bare TiO2 nanoparticles, which is absent in the PDMS-coated TiO2 hydrophobic surface. Further, the results of UV–vis absorption spectra (Figure S3D) show that the prepared inorganic matrix absorbs UV light below 390 nm, which deflects that PDMS coating did not affect the optical properties of a TiO2 surface.

To further confirm the hydrophobicity of PDMS-coated TiO2, the water contact angle was measured. The water contact angle of the bare TiO2 nanoparticle surface was difficult to measure due to the hydrophilic properties of TiO2. However, the water contact angle of the PDMS-coated TiO2 nanoparticle surface was measured to be 128.4° (Figure S4B). The modification of the hydrophilic surface of bare TiO2 to PDMS-coated TiO2 caused a hydrophobic surface to be developed. For the solubility check, the bare and PDMS-coated TiO2 nanoparticles were dissolved in DI water. The results showed that the hydrophilic surface of the bare TiO2 nanoparticles became hydrophobic because of the PDMS polymer coating (Figure S4C).

Binding of Modulated Peptides to the PDMS Surface

To study the hydrophobic interaction between peptides and PDMS, the SALDI-TOF simulation was performed using a newly developed inorganic PDMS-coated TiO2 matrix. The signal intensity of all peptide candidates on the PDMS-coated TiO2 matrix was higher than that on the bare TiO2 matrix due to an increase in the hydrophobicity of the matrix. The SALDI-TOF signal intensity indicates the number of peptides bound to the matrix, which reflects a binding affinity with the matrix molecule. The SALDI-TOF signal intensity increases when the polar amino acid is mutated to a hydrophobic amino acid at a similar molecular weight of the peptides. A similar pattern of increasing hydrophobicity in peptides induced by more binding to the PDMS surface was observed with all the three-length candidates, as shown in Figure 1B–D.

In the PBP-7aa candidates with a random coil structure, PBP-7aa-Mut was bound to PDMS 10.5 times more than PBP-7aa-Nat (Figure 1B). Surprisingly, the mutation in just one residue (E to I) highly affected the binding affinity increase. In contrast, PBP-21aa-Mut with a fully α-helix structure bound to PDMS 4.7 times more than PBP-21aa-Nat, despite the mutation of three residues for an increase in hydrophobicity (Figure 1D). In PBP-14aa with partially α-helix and partially random coil structures, mutations increase the binding affinity 8.1 times higher than fully α-helix structures and lower than fully random coil structures. SALDI-TOF results showed the same increase in hydrophobicity in PBP-7aa and PBP-21aa, which had different mutation effects due to the secondary structure of peptides. Our results suggest that the flexibility of random coil structures maximizes the mutation effect for hydrophobic interactions, while the structural stability of α-helix structures has less effect on mutation.

To gain insights into the structural effectiveness of interaction with the hydrophobic surface of PDMS and confirm the correspondence of experimental and theoretical approaches, MD simulations were performed (Figure 2A). Based on the MD simulation results, the analysis of the secondary structure of peptides on PDMS and the calculation of binding affinity between peptides and PDMS were performed. The peptides were quickly adsorbed on the PDMS surface (Figure S6), and the binding energy was calculated using the molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) method. The total binding energy between peptides of different lengths and PDMS increases after mutation from polar amino acid to hydrophobic amino acid (Figure 2B). Through a detailed investigation of the results, it can be deduced that the main driving force of the adsorption is van der Waals interactions as they are consistently increased by increasing the hydrophobicity of the modulated peptides. The van der Waals interaction in total binding energy showed a high energy increase, whereas electrostatic repulsion decreased by mutation from a charged amino acid to a hydrophobic amino acid.

Figure 2.

Figure 2

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(A) System for simulations mimicking adsorption of modulated peptides. (B) The binding affinity of peptide candidates was calculated with both the experimental method (SALDI-TOF) and theoretical method (MD simulation; binding energy of peptides with the PDMS surface). Fold change is calculated by dividing the intensity of the Mut candidate by the intensity of the Nat candidate.

As a result, the SALDI-TOF and MD simulation results correspond in terms of binding affinity between peptides and PDMS (Figure 2B). Like the SALDI-TOF result, the mutation effect was different at the three lengths of a peptide. The seven amino acid length peptides with a random coil structure (PBP-7aa) had the biggest increase in hydrophobic interaction in both experimental and theoretical measurements (10.5 and 13.7 folds, respectively). In contrast, the 21 amino acid length peptides with a fully α-helix structure (PBP-21aa) had the smallest mutation effect in experimental and theoretical measurements (4.7 and 3.8 folds, respectively).

After 500 ns simulations, the positively charged amino acids headed for the solvent interface and did not interact with the PDMS surface in PBP-7aa-Nat and PBP-21aa-Nat. After mutation from a positively charged amino acid to a hydrophobic amino acid, the mutated residue headed for and interacts with the PDMS surface in both PBP-7aa-Mut and PBP-21aa-Mut. However, the conformational change in the peptide was different as the secondary structure was either a random coil or an α-helix (Figure 3A,B). In the case of PBP-7aa with a random coil structure, the mutated residue changed the position and increased the binding affinity (Figure 3D,E). In the case of PBP-21aa with an α-helix structure, the entire α-helix structure was rotated for interaction between mutated residues and the PDMS surface (Figure 3B). The interactions between mutated residues and the PDMS surface increased, and the overall interaction network changed (Figure 3E). These differences in interaction network changes after the mutation induced higher binding energy in PBP-7aa than in PBP-21aa.

Figure 3.

Figure 3

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Structural and energetic analyses of peptide adsorption on PDMS via MD simulations. Representative structures of (A) PBP-7aa and (B) PBP-21aa candidates after 500 ns equilibrium simulations. (C) Secondary structure analysis during the last 50 ns simulations. (D,E) Binding energy of each residue in (D) PBP-7aa and (E) PBP-21aa with the PDMS surface before and after mutations.

The secondary structure at each amino acid of six peptide candidates is analyzed using STRIDE software, which is used to determine the secondary structures while considering the hydrogen bond interaction and the dihedral angle of the peptide backbone (Figures 3C and S7). In the case of 7 and 21 amino acid length peptides, they did not exhibit any difference in the secondary structure before and after the mutation of a polar amino acid to a hydrophobic amino acid (a fully random coil or a fully α-helix structure, respectively). The 14 amino acid length peptide and a slightly unfolded α-helix structure showed structural folding to α-helix near the mutated sequence site. These results conclude that more unfolding of the secondary structure caused by a reduction in the number of amino acids maximizes the effect of mutation for increasing the hydrophobic interaction with the PDMS surface. This has been correlated with circular dichroism, which can observe the secondary structure of the modulated peptide. 7aa-Nat and 7aa-Mut were random coils that showed negative ellipticity at 200 nm, while the longer peptides, 14aa and 21aa, showed a significant increase in α-helical propensity, and mutated candidates did not cause a conformational change compared to the native sequence.

Conclusions

The hydrophobic interactions between peptides and hydrophobic solid surfaces were first demonstrated at the atomic level via both experimental and theoretical methods employing a newly developed hydrophobic solid matrix and MD simulations. To control the secondary structure of peptides and hydrophobicity, we made their modulation by changing the length of amino acids and mutating polar amino acids into hydrophobic amino acids. We could decouple the parameters of the hydrophobic effect on a surface with sequence and structure. When the peptide has low structural robustness, the mutation effects are maximized in hydrophobic interactions with the hydrophobic surface, but when the structure is well folded, the hydrophobicity of the interface is less effective than the flexible secondary structure. Our work provides insights into the design or modulation principles of peptide adsorption on the hydrophobic surface of nanomaterials, which may open novel ways for developing innovative biomimetic and biocompatible applications.

Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2021R1A4A1033424, 2022R1A4A1019296); and the Bio & Medical Technology Development Program of the National Research Foundation (NRF) (No. 2020M3A9E4039217); and Nano·Material Technology Development Program through the NRF funded by the MSIP of Korea (No. 2017M3A7B4041973); and Korea Basic Science Institute (National research Facilities and Equipment Center) grant funded by the Ministry of Education (No. 2022R1A6C101A751).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c03934.

  • Secondary structure analysis, hydrophobicity of peptides, properties of the PDMS-coated TiO2 matrix, and experimental data for SALDI-TOF measurements (PDF)

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Y.H.N., N.H.K., M.S.Z., and S.H.P. contributed equally.

The authors declare the following competing financial interest(s): Y.H.K. and J.L. are Vice President of Imnewrun INC. and may have competing financial interest. N.H.K. receives research fellowship grant from IMNEWRUN INC.

Supplementary Material

ao2c03934_si_001.pdf (882.9KB, pdf)

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