Development Of Fragment Quantum Chemical Method And Theoretical Studies On Vibrational Stark Effect For Proteins

Protein plays a crucial role in the activities of lives. The studies of protein structures and functions have considerable medicinal and industrial applications. The electric fields produced by the charged and polar groups of protein have been considered as the main source of molecular interaction and influence nearly every aspect of protein structures and functions. Many theoretical and experimental works have been carried out to study the electrostatic of protein. Vibrational Stark effect (VSE) spectroscopy has been widely used to study the change of protein dynamic behaviors. Linear Stark effect gives the direct relationship between spectrum and electric field. Utilizing some specific-group-containing probes that can deliver a unique Stark vibration to the specific site of interest in the protein it is practical to experimentally reveal the change of electrostatic properties in the matrix of protein. With the help of molecular dynamics (MD) simulations based on force field, computer simulation has emerged as a powerful tool to study properties of protein. Despite much success in applications of standard force fields such as CHARMM, Amber, and OPLS, there is a fundamental limitation due to the lack of electronic polarization effects. The charge models in this force field are mean-field-like and do not include polarization effect due to the specific protein environment The contribution of the polarization effect could be neglected in some cases, while more and more theoretical works indicate its importance in the calculation of protein properties. Molecular dynamics simulations were carried out to compute linear Stark shift in human aldose reductase (hALR2) using a recently developed polarized protein-specific charge (PPC) model derived from quantum-chemistry calculations so as to include polarization effect due to the specific protein environment. The same calculations but based on conventional nonpolarizable Amber force field were also carried out. Our study demonstrates that the Stark shifts calculated based on the PPC model are in much better agreement with the experimental measured data than widely used nonpolarizable force fields, indicating that the electronic polarization effect is important for the accurate prediction of changes in the electric field inside proteins and traditional force field has still room for improvement for capturing the electrostatics of protein.Our study of internal electric field and stark spectroscopy of protein indicates that the classical force field model after correction by high-level quantum chemistry calculation would give better agree with experimental results. It is well kown that in the existing theoretical methods, the calculations based on quantum mechanics (QM) could give very accurate and reliable results. For small systems one can achieve the desired calculation at either the chemical or even the spectroscopic accuracy level using appropriate methods. Theoretical chemists hope to perform quantum mechanics (QM) calculations on large molecular systems. Recent years, although the development of computer make it possible to perform quantum mechanics (QM) calculations on molecule that contain hundreds or even thousands of atoms, atoms contained in the molecule studied in many scientific researches are far more than this number. For example, it is still a grand challenge in computational chemistry to apply conventional quantum mechanical methods for large protein systems. For this problem, a linear-scaling quantum mechanical method called Molecular Fractionation with Conjugate Caps (MFCC) has been proposed and it has been used in many aspects of calculations of protein properties. In order to calculate the energy of proteins more accurately a generalized molecular fractionation with conjugate caps/MM (GMFCC/MM) method is developed. Based on which an Electrostatically Embedded Generalized Molecular Fractionation with Conjugate Cap (EE-GMFCC) method was developed for further improving the computing accuracy. In the EE-GMFCC scheme, the total energy of protein is calculated by taking a linear combination of the QM energy of each fragment. All the fragment calculations are embedded in a field of point charges representing the remaining protein environment. Calculations of energy using the EE-GMFCC approach at the HF/6-31G*level are carried out on18real three-dimensional proteins. The overall mean unsigned error of EE-GMFCC for these18proteins is2.39kcal/mol with reference to the full system HF/6-31G*energies. The EE-GMFCC approach is also tested for proteins at the density functional theory (DFT) and second order many-body perturbation theory (MP2) level, also showing only a few kcal/mol deviation from the corresponding full system result. For protein that contains hundreds of atoms, our EE-GMFCC method shows a distinct advantage in the consumption of computing time when compared with conventional full system calculation and makes it possible to perform quantum mechanics (QM) calculations on protein molecule of any size.Internal electric field inside a protein affects its structure, function and dynamics, while external electric field has a same significant effect on conformational integrity of protein. Some experimental works has confirmed that microwave radiation could alter protein conformation without bulk heating. Currently, the nonthermal effect of external electric fields acting on proteins has attracted a lot of theoretical and experimental research interest. While for traditional experimental approaches, it is still difficult to provide the details at the atomic level. By means of molecular simulation method computer simulation could give more detailed interpretation for dynamic behavior of peptides or proteins in external electric field. We perform a series of molecular dynamics (MD) simulations up to one μs for bovine insulin monomer in different external electric field. Our results indicated that the secondary structure of insulin is kept intact under the action of external electric field strength below0.15V/nm, but disruption of secondary structure would be observed at0.25V/nm or higher electric field. The corralation is not obvious between the starting time of secondary structure disruption of insulin and the strength of the external electric field ranging between0.15to0.60V/nm. Long time MD simulation up to one μs shows that the cumulative effect of exposure time under the electric field is a major cause for the damage of insulin’s secondary structure. In addition, the strength of the external electric field has a significant impact on the lifetime of hydrogen bonds when it is higher than0.60V/nm. The fast evolution of some hydrogen bonds of bovine insulin in the presence of1.0V/nm electric field suggests that different microwaves could either speed up protein folding or destroy the secondary structure of globular proteins deponding on the intensity of the external electric field.