Biomolecular simulation is increasingly central to understanding and designing biological molecules and their interactions. Detailed, physics‐based simulation methods are demonstrating rapidly ...growing impact in areas as diverse as biocatalysis, drug delivery, biomaterials, biotechnology, and drug design. Simulations offer the potential of uniquely detailed, atomic‐level insight into mechanisms, dynamics, and processes, as well as increasingly accurate predictions of molecular properties. Simulations can now be used as computational assays of biological activity, for example, in predictions of drug resistance. Methodological and algorithmic developments, combined with advances in computational hardware, are transforming the scope and range of calculations. Different types of methods are required for different types of problem. Accurate methods and extensive simulations promise quantitative comparison with experiments across biochemistry. Atomistic simulations can now access experimentally relevant timescales for large systems, leading to a fertile interplay of experiment and theory and offering unprecedented opportunities for validating and developing models. Coarse‐grained methods allow studies on larger length‐ and timescales, and theoretical developments are bringing electronic structure calculations into new regimes. Multiscale methods are another key focus for development, combining different levels of theory to increase accuracy, aiming to connect chemical and molecular changes to macroscopic observables. In this review, we outline biomolecular simulation methods and highlight examples of its application to investigate questions in biology.
This article is categorized under:
Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo Methods
Structure and Mechanism > Computational Biochemistry and Biophysics
Molecular and Statistical Mechanics > Free Energy Methods
Biomolecular simulations reveal mechanisms, dynamics, and interactions of biological molecules. Here, molecular dynamics simulation of the enzyme MalL reveal structural and dynamical changes in the protein during its catalytic cycle; these simulations allow calculation of the activation heat capacity that explains the optimum temperature of its catalytic activity.
Abstract Introduction Transient receptor potential (TRP) channels are broadly expressed cation channels that mediate diverse physiological stimuli and include canonical (TRPC), melastatin (TRPM) and ...vanilloid (TRPV) subtypes. Recent studies have implicated a role for TRPC6 channels as an important component of signaling via the cytokine, transforming growth factor beta 1 (TGFb1) in right (RV) or left ventricular (LV) failure. Endoglin is a transmembrane glycoprotein that promotes TRPC6 expression and TGFb1 activity. No studies have defined biventricular expression of all TRP channel family members in heart failure. Hypothesis We hypothesized that heart failure is associated with distinct patterns of TRP channel expression in the LV and RV. Methods Paired viable left (LV) and right (RV) ventricular free wall tissue was obtained from human subjects with end-stage heart failure (n=12) referred for cardiac transplantation or biventricular assist device implantation. Paired LV and RV samples from human subjects without heart failure served as controls (n=3). To explore a functional role for endoglin (Eng) as a regulator of TRP expression in response to RV or LV pressure overload, wild-type (Eng+/+) and Eng haploinsufficient (Eng+/−) mice were exposed to thoracic aortic (TAC) or pulmonary arterial (PAC) constriction for 8 weeks. Biventricular tissue was analyzed by real-time polymerase chain reaction. Results Compared to non-failing human LV and RV samples, mRNA levels of TRPC1, 3, 4, 6 and TRPV-2 were increased and TRPM2, 3, and 8 were decreased in failing LV and RV samples. TRPC1 and 6 levels were higher in failing RV compared to failing LV samples. After TAC, murine LV levels of TPRC1 and 6 were increased in both Eng +/+ and Eng +/− mice compared to sham controls. LV levels of TRPC4; TRPM3 and 7; TRPV2 and 4 were increased in Eng +/+, not Eng +/− mice after TAC. After PAC, all TRP channel family members were increased in the RV, but not LV, of Eng +/+ compared to sham controls. In contrast to Eng+/+, PAC did not increase RV or LV levels of TRP channels in Eng +/− mice. Conclusions This is the first study to demonstrate that TRP channels exhibit distinct profiles of expression in the LV and RV of patients with heart failure and in murine models of univentricular pressure overload. We further introduce that the TGFb1 co-receptor endoglin selectively regulates expression of multiple TRP channels in the setting of LV or RV pressure overload.
Background Persistence of pigmentation after a melanocyte-keratinocyte transplantation procedure (MKTP) is an important consideration for efficacy. Objective We sought to determine long-term ...repigmentation of MKTP in vitiligo and other leukodermas. Methods A retrospective review of electronic medical records was conducted for all MKTPs performed at Henry Ford Hospital between January 2009 and April 2014. Repigmentation was assessed by a 5-point grading scale (poor to excellent) and Vitiligo Area Scoring Index (VASI). Results One hundred patients had MKTP performed at 236 anatomically-based lesions (ABLs); 63 patients with 157 ABLs had long-term data available (12-72 months; median, 24 months). Segmental vitiligo, nonsegmental vitiligo, and physical leukoderma demonstrated improvement in VASI scores: −75.6 ± 24.6%, −59.2 ± 36.6%, and −32.4 ± 33.5%, respectively. In vitiligo, at 24, 48, and 72 months after MKTP, 53%, 64%, and 53% of ABLs, respectively, maintained >75% repigmentation. Skin phototype, age, and anatomic location of ABLs had no significant effect on the outcome of treatment. Limitations Limitations of the study include the retrospective design with uncontrolled, postoperative adjuvant treatments and inconsistent compliance to scheduled follow-up evaluations. Conclusions MKTP provides satisfactory long-term repigmentation in the majority of appropriately selected patients with leukoderma. MKTP can maintain repigmentation for at least 72 months.
The Vitiligo Area Scoring Index (VASI) is a tool for measuring repigmentation after patients undergo vitiligo treatment, offering a standardized, quantitative scale without the need for specialized ...equipment. For large multicentre trials that require multiple raters, VASI must be consistently applied to generate interpretable data; therefore, a method for assessing rater reliability would improve data integrity for large clinical studies of vitiligo. This study aimed to assess a method for determining the reliability of VASI raters by evaluating raters of different levels of experience relative to a gold standard.
Background Vitiligo is a disfiguring disease with limited treatment options. Surgical treatment is underused in the United States because of perceived risk of infection, costs, and difficulty of the ...procedure. Objective We sought to determine the efficacy and safety of the melanocyte-keratinocyte transplantation procedure (MKTP) in an academic dermatology department in the United States. Methods This prospective, uncontrolled, open-label study enrolled patients aged 18 years or older with a self-reported history of vitiligo and no new or expanding lesions for at least 6 months before surgery. Patients with a history of koebnerization or keloid formation were excluded. Patients underwent autologous MKTP. Repigmentation during a 3- to 6-month follow-up period was assessed categorically and by modified Vitiligo Area Scoring Index. Safety was assessed by frequency of adverse events. Results Of the 28 patients who underwent 36 procedures, 23 patients who underwent 29 procedures completed the 3- to 6-month follow-up period. Data for these 29 procedures show excellent repigmentation (ie, 95%-100%) after the MKTP in 17%, and good repigmentation (ie, 65%-94%) in 31%. Fair (64%-25%) and poor (24%-0%) repigmentation were achieved in 10% and 41% of patients, respectively. Average percent change in Vitiligo Area Scoring Index was −45% (95% confidence interval −64% to −26%), signifying an improvement in pigmentation. Limitations Limitations include small sample size and lack of a control group. Conclusions The MKTP is an effective and well-tolerated procedure based upon categorical and Vitiligo Area Scoring Index assessments of repigmentation.
In the United States, many individual vitiligo support groups have collaborated on a joint national US World Vitiligo Day since 2016. As part of the 2020 and 2021 US World Vitiligo Day virtual ...events, polls were conducted that solicited information from participants regarding their life with vitiligo. A majority (76% in 2020; 92% in 2021) would like a cure for vitiligo. In 2020 and 2021, 40% and 35% responded they both show and hide their vitiligo when asked how they display their skin. A minority, 14% in 2020 and 5% in 2021, reported their vitiligo treatments were fully covered by their insurance. When polled about acceptance, in 2021, 40% reported they were accepting of their vitiligo most days. In 2021, 20% were interested in trying treatments, even if they included moderate side effects and 29% were interested, if minimal side effects. Results herein suggest that while many patients are accepting of their disease, many also want a cure. Additionally, dermatologists should advocate for coverage of vitiligo treatment, while also taking insurance coverage into account when discussing treatment options. Further, vitiligo patients require individualized care considering some patients may be open to attempting more aggressive treatment, despite the side effect profiles, while others are not interested in treatment or only willing to attempt treatments without side effects.
Summary
Although non‐segmental vitiligo (NSV) results from the autoimmune destruction of melanocytes, the detailed immune mechanisms have not yet been fully elucidated. Th17 cells have been ...identified to be implicated in human autoimmune diseases. In this study, the frequencies of peripheral blood Th17 cells and serum levels of IL‐17A and Th17 cell‐related cytokines were examined in 45 patients with active NSV compared to 45 race‐, gender‐, and age‐matched healthy controls. Our results showed increased circulating Th17 cell frequencies and elevated serum IL‐17A, TGF‐β1, and IL‐21 levels in patients with NSV. Meanwhile, the increased Th17 cell frequencies are positively correlated with serum TGF‐β1 level, and the body surface area of lesions is positively correlated with elevated TGF‐β1 and IL‐21 levels and Th17 cell frequencies. Furthermore, positive correlation was identified between Th17 and Th1 cell frequencies in patients with NSV. These results further indicate the potential involvement of Th17 cells and the collaborative contribution of Th17 and Th1 in NSV development, and suggest that the elevated serum TGF‐β1 and IL‐21 levels could contribute to enhanced Th17 cell differentiation in NSV.
Starting and maintaining a vitiligo support group can appear to be a daunting task. However, with proper planning and organization, the process can become manageable and rewarding. Our guide details ...the reasons to start a vitiligo support group, how to start a group, how to run a group, and how to promote a group. Legal protections and details regarding retention and funding are also discussed. The authors have extensive experience leading and/or assisting support groups for vitiligo and other disease states and we also sought out other current vitiligo support leaders for their valuable insights. Previous research has found that support groups for various medical conditions may have a protective effect and membership can build resilience among participants as well as foster a sense of hope regarding their disease. Further, groups can provide a network for those living with vitiligo to connect with, uplift, and learn from one another. These groups provide the opportunity to initiate lifelong connections with those facing similar circumstances and provide members with new insight and coping strategies. Members can share perspectives with one another and empower one another. We encourage dermatologists to provide vitiligo patients with support group information and to consider being involved in, starting, or otherwise supporting them.
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